To the editor:

Novel approaches targeting molecules involved in intracellular pathways that are crucial for the survival and proliferation of the leukemic clone have been recently approved for the treatment of chronic lymphocytic leukemia (CLL) patients. Nevertheless, CLL remains incurable outside of allogeneic stem cell transplant, and novel treatment options for relapsed/refractory patients remain an unmet clinical need. Cyclin-dependent kinases (CDKs), key regulators of cell cycle progression, have become attractive therapeutic targets in oncology and hematology,1,2  given the role of aberrant cell cycle regulation in the pathogenesis of many cancers, including leukemias. CDK inhibitors offer the potential of simultaneous blockade of cell cycle progression and transcription, facilitating the induction of apoptosis and reactivation of the TP53 tumor suppressor mechanism. These agents have shown potent activity in patients with CLL.3  The pan-CDK inhibitor flavopiridol demonstrated clinical efficacy4,5  but was associated with tumor lysis syndrome (TLS), which occurred in 25% of patients, some of whom required hemodialysis.6 

Dinaciclib is a novel, potent, small-molecule CDK inhibitor that selectively inhibits CDK1, 2, 5, and 9 at 50% inhibitory concentration values in the 1- to 4-nM range.7,8  In in vitro studies, dinaciclib induced apoptosis and/or cell growth arrest in various solid and hematopoietic tumor cell models.9-11  Additionally, dinaciclib produces caspase-independent downregulation of messenger RNA and protein expression of the antiapoptotic protein myeloid cell leukemia 1 (MCL1), which is essential for CLL cell survival.12  In murine xenograft models, dinaciclib exhibited a superior therapeutic index compared with flavopiridol.9  Phase 1 studies of dinaciclib demonstrated acceptable toxicity, with typical adverse events (AEs) represented by cytopenias, transient laboratory abnormalities, and TLS.13,14  A phase 1 study of dinaciclib in patients with CLL showed a partial response rate of ∼63% in pretreated subjects at the recommended phase 2 dose (14 mg/m2),13  including responses in high-risk subgroups, such as patients with deletion of 17p (del17p).13 

Ofatumumab is a fully humanized type I anti-CD20 monoclonal antibody,15,16  which binds to a different epitope of CD20 than rituximab.17  A phase 1/2 study in relapsed/refractory CLL demonstrated that ofatumumab had an overall response rate (ORR) of 50% and was generally well tolerated, even at high doses.18  Ofatumumab has shown activity in subjects with fludarabine- and alemtuzumab-refractory and bulky fludarabine-refractory CLL, irrespective of prior treatment with rituximab.19  However, the phase 3 RESONATE trial demonstrated a remarkably lower ORR in patients with relapsed/refractory CLL treated with ofatumumab (4.1%; used as control arm vs ibrutinib).20 

Here, we present the results of a randomized, open-label, phase 3 trial designed to compare the efficacy and tolerability of dinaciclib with ofatumumab in patients with relapsed/refractory CLL (registered at www.clinicaltrials.gov as #NCT01580228; study P012). At the time of study initiation, ofatumumab was the only therapy specifically approved for refractory CLL patients and was therefore selected as the comparison arm. Patients with confirmed CLL, as defined by the 2008 International Workshop on CLL criteria,21  and no response or disease relapse within 6 or 24 months after fludarabine or chemoimmunotherapy, respectively, were enrolled. Dinaciclib was administered IV at escalating doses of 7 to 10 to 14 mg/m2 (on days 1, 8, and 15, respectively) in cycle 1 and 14 mg/m2 in cycle 2 and thereafter (1 cycle = 28 days) for 12 cycles. Ofatumumab was administered IV once weekly for 8 weeks starting in cycle 1 on day 1, followed by 9 monthly doses as follows: 300 mg in cycle 1 on day 1; 2000 mg in cycle 1 on days 8, 15, and 22 and cycle 2 on days 1, 8, 15, and 22, and every 4 weeks starting from 5 weeks later on day 1 of cycles 4 to 12. The trial was designed to evaluate progression-free survival (PFS) as the primary end point (ORR, partial response + complete response) and overall survival (OS) in patients with relapsed/refractory CLL treated with dinaciclib compared with ofatumumab. Safety and tolerability were assessed by clinical review of all relevant parameters, including AEs, laboratory tests, vital signs, and electrocardiographic measurements. Complete details regarding trial methodology are provided in supplemental Materials (available on the Blood Web site).

Early termination of the study due to program prioritization and unrelated to safety or efficacy issues occurred, but collected data are reported here. Overall, 44 patients were randomized (intention to treat) and 42 were treated (supplemental Figure 1). Approximately 284 to 466 subjects (186 del17p; 98 to 280 non-del17p) were originally planned for enrollment. Patient characteristics at baseline are presented in Table 1. The median follow-up duration (range) was 16.7 (0.4-26.1) months.

Table 1.

Baseline demographics and disease characteristics

Dinaciclib (n = 20)Ofatumumab (n = 22)Total (n = 42)
Sex (male) 15 (75.0) 17 (77.3) 32 (76.2) 
Age, mean ± SD, y 60.1 ± 8.6 62.3 ± 9.1 61.2 ± 8.8 
Race    
 White 19 (95.0) 20 (90.9) 39 (92.9) 
 Other 1 (5.0) 2 (9.0) 3 (7.2) 
Rai stage    
 I 1 (5.0) 2 (9.1) 3 (7.1) 
 II 4 (20.0) 8 (36.4) 12 (28.6) 
 III 1 (5.0) 5 (22.7) 6 (14.3) 
 IV 13 (65.0) 7 (31.8) 20 (47.6) 
 Missing 1 (5.0) 0 (0.0) 1 (2.4) 
Number of prior therapies, median (range) 2 (1-6) 3 (1-20) 3 (1-20) 
Prior fludarabine 18 (90.0) 21 (95.5) 39 (92.9) 
Prior rituximab 19 (95.0) 22 (100.0) 41 (97.6) 
Bulky disease* 12 (60.0) 12 (54.5) 24 (57.1) 
ECOG <1 18 (90.0) 22 (100.0) 40 (95.2) 
Del17p 7 (35.0) 9 (40.9) 16 (38.1) 
Refractory/relapse    
 Chemoimmunotherapy ≤6 mo 14 (70.0) 13 (59.1) 27 (64.3) 
 Fludarabine refractory 3 (15.0) 3 (13.6) 6 (14.3) 
 Chemoimmunotherapy >6 to 24 mo 3 (15.0) 6 (27.3) 9 (21.4) 
Dinaciclib (n = 20)Ofatumumab (n = 22)Total (n = 42)
Sex (male) 15 (75.0) 17 (77.3) 32 (76.2) 
Age, mean ± SD, y 60.1 ± 8.6 62.3 ± 9.1 61.2 ± 8.8 
Race    
 White 19 (95.0) 20 (90.9) 39 (92.9) 
 Other 1 (5.0) 2 (9.0) 3 (7.2) 
Rai stage    
 I 1 (5.0) 2 (9.1) 3 (7.1) 
 II 4 (20.0) 8 (36.4) 12 (28.6) 
 III 1 (5.0) 5 (22.7) 6 (14.3) 
 IV 13 (65.0) 7 (31.8) 20 (47.6) 
 Missing 1 (5.0) 0 (0.0) 1 (2.4) 
Number of prior therapies, median (range) 2 (1-6) 3 (1-20) 3 (1-20) 
Prior fludarabine 18 (90.0) 21 (95.5) 39 (92.9) 
Prior rituximab 19 (95.0) 22 (100.0) 41 (97.6) 
Bulky disease* 12 (60.0) 12 (54.5) 24 (57.1) 
ECOG <1 18 (90.0) 22 (100.0) 40 (95.2) 
Del17p 7 (35.0) 9 (40.9) 16 (38.1) 
Refractory/relapse    
 Chemoimmunotherapy ≤6 mo 14 (70.0) 13 (59.1) 27 (64.3) 
 Fludarabine refractory 3 (15.0) 3 (13.6) 6 (14.3) 
 Chemoimmunotherapy >6 to 24 mo 3 (15.0) 6 (27.3) 9 (21.4) 

Data are presented as n (%) of patients, unless otherwise indicated.

ECOG, Eastern Cooperative Oncology Group.

*

Defined as any lymph node >5 cm by physical exam or computed tomography scan.

The results informing PFS, ORR, and OS signaled promising antileukemia activity with dinaciclib relative to ofatumumab (Table 2), although the limited sample size precluded the conduct of planned statistical analyses. Median PFS was 13.7 and 5.9 months for patients receiving dinaciclib and ofatumumab, respectively. The ORR was 40.0% for patients receiving dinaciclib and 8.3% for those receiving ofatumumab; all were partial responses. Stable disease was achieved by 35.0% of dinaciclib and 45.8% of ofatumumab patients. Median OS was 21.2 and 16.7 months for patients receiving dinaciclib and ofatumumab, respectively.

Table 2.

Progression-free survival and response to treatment

Dinaciclib (n = 20)Ofatumumab (n = 24)
PFS   
 PFS events* 11 (55.0) 17 (70.8) 
 Person-months 213 135 
 Event rate/100 person-months, % 5.2 12.6 
 Median PFS, months (95% CI) 13.7 (10.3, 21.2) 5.9 (2.1, 9.4) 
Response to treatment   
 Complete 0 (0.0) 0 (0.0) 
 Partial 8 (40.0) 2 (8.3) 
 Overall response 8 (40.0) 2 (8.3) 
 Stable disease 7 (35.0) 11 (45.8) 
 Progressive disease 1 (5.0) 1 (4.2) 
 Not evaluable§ 4 (20.0) 10 (41.6) 
Dinaciclib (n = 20)Ofatumumab (n = 24)
PFS   
 PFS events* 11 (55.0) 17 (70.8) 
 Person-months 213 135 
 Event rate/100 person-months, % 5.2 12.6 
 Median PFS, months (95% CI) 13.7 (10.3, 21.2) 5.9 (2.1, 9.4) 
Response to treatment   
 Complete 0 (0.0) 0 (0.0) 
 Partial 8 (40.0) 2 (8.3) 
 Overall response 8 (40.0) 2 (8.3) 
 Stable disease 7 (35.0) 11 (45.8) 
 Progressive disease 1 (5.0) 1 (4.2) 
 Not evaluable§ 4 (20.0) 10 (41.6) 

Data are presented as n (%) of patients, unless otherwise indicated. Small sample sizes due to early study termination precluded testing of statistical significance.

CI, confidence interval.

*

PFS is defined as the time from randomization to disease progression or death, whichever occurred first.

From product-limit (Kaplan-Meier) method for censored data.

Patients’ best response to therapy, according to investigator assessment across time points per the 2008 International Workshop on CLL criteria.

§

Patients were required to have at least 2 postbaseline scans for an evaluable response.

Interestingly, dinaciclib was similarly effective in the del17p subgroup of patients (n = 7) compared with the overall study population. In this subgroup, median PFS was 17.2 and 2.4 months and median OS was 21.2 and 5.4 months in patients receiving dinaciclib and ofatumumab, respectively. Del17p has consistently been associated with poor response to chemotherapy, decreased OS,22  and earlier relapse despite treatment with novel B-cell receptor inhibitors.23 

Dinaciclib had an acceptable safety and tolerability profile in patients with relapsed/refractory CLL (supplemental Tables 1 and 2). The observed AEs were consistent with those previously identified in patients with relapsed/refractory CLL,13  especially considering that the study population received a median of 3 previous lines of treatment before enrollment into the study. The most common grade ≥3 AEs with dinaciclib and ofatumumab, respectively, were neutropenia (35.0% vs 9.1%), thrombocytopenia (20.0% vs 9.1%), decreased neutrophil count (20.0% vs 4.5%), pneumonia (5.0% vs 13.6%), sepsis (5.0% vs 13.6%), and febrile neutropenia (10.0% vs 4.5%). TLS has been observed with other CDK inhibitors in the treatment of CLL and may be the result of sensitivity of the CLL cells to this class of agents.24  Only 1 patient in the dinaciclib group developed a laboratory TLS25 ; this event was deemed not treatment related by the study investigator.

This study provides important insight into the potential antileukemic activity and signals an acceptable safety and tolerability profile of dinaciclib compared with ofatumumab in patients with relapsed/refractory CLL, even among high-risk subgroups. The tolerability of dinaciclib appears to be strongly improved in comparison with first-generation CDK inhibitors, especially with respect to the occurrence of TLS. Whereas these data are encouraging, the efficacy results from this small, terminated trial are insufficient to definitively conclude that dinaciclib provides superior anticancer activity vs ofatumumab in patients with relapsed/refractory CLL. Nevertheless, based on these results and given the distinct mechanism of action directed against CDK while allowing for downregulation of MCL1, further studies investigating dinaciclib are warranted. In particular, combinations with other novel agents for the treatment of CLL are currently being explored in clinical trials.

Presented in part at the 57th annual meeting of the American Society of Hematology, Orlando, FL, 5-8 December 2015.

The online version of this article contains a data supplement.

Authorship

Acknowledgments: The authors thank Sheila Erespe (Merck & Co., Inc., Kenilworth, NJ) for editorial assistance.

The study was sponsored by Merck & Co., Inc.

Contribution: P.G., S.P., M.D., and K.S. designed or planned the study; S.P. and N.P. acquired the data; P.G., L.S., S.P., K.P., and M.D. analyzed the data; P.G., L.S., S.P., K.P., K.S., C.M.S., and N.P. interpreted the data; P.G., K.P., and C.M.S. drafted the manuscript; and all authors critically revised the manuscript for important intellectual content. All authors have reviewed the submitted version of the manuscript and agree with its content and submission, had access to all relevant study data, vouch for the accuracy and completeness of the data presented, agree to be accountable for all aspects of the work, and will ensure that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Conflict-of-interest disclosure: P.G. received personal fees from Merck & Co., Inc. (during the conduct of the study), as well as personal fees from AbbVie, Adaptive Biotechnologies, Janssen, and Pharmacyclics; grants from GSK and Celgene; and grants and personal fees from Roche and Gilead (outside the submitted work). L.S. received personal fees from Janssen, Gilead, and Roche (outside the submitted work). S.P., K.P., M.D., K.S., and C.M.S. are current employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., and hold stock and stock options in the company. N.P. declares no competing financial interests.

Correspondence: Paolo Ghia, Università Vita-Salute San Raffaele, Via Olgettina 58, 20132 Milan, Italy; e-mail: ghia.paolo@hsr.it.

References

References
1.
Malumbres
M
,
Barbacid
M
.
Cell cycle, CDKs and cancer: a changing paradigm
.
Nat Rev Cancer
.
2009
;
9
(
3
):
153
-
166
.
2.
Shapiro
GI
.
Cyclin-dependent kinase pathways as targets for cancer treatment
.
J Clin Oncol
.
2006
;
24
(
11
):
1770
-
1783
.
3.
Cicenas
J
,
Valius
M
.
The CDK inhibitors in cancer research and therapy
.
J Cancer Res Clin Oncol
.
2011
;
137
(
10
):
1409
-
1418
.
4.
Phelps
MA
,
Lin
TS
,
Johnson
AJ
, et al
.
Clinical response and pharmacokinetics from a phase 1 study of an active dosing schedule of flavopiridol in relapsed chronic lymphocytic leukemia
.
Blood
.
2009
;
113
(
12
):
2637
-
2645
.
5.
Lin
TS
,
Ruppert
AS
,
Johnson
AJ
, et al
.
Phase II study of flavopiridol in relapsed chronic lymphocytic leukemia demonstrating high response rates in genetically high-risk disease
.
J Clin Oncol
.
2009
;
27
(
35
):
6012
-
6018
.
6.
Lanasa
MC
,
Andritsos
L
,
Brown
JR
, et al
.
Final results of EFC6663: a multicenter, international, phase 2 study of alvocidib for patients with fludarabine-refractory chronic lymphocytic leukemia
.
Leuk Res
.
2015
;
39
(
5
):
495
-
500
.
7.
Nemunaitis
JJ
,
Small
KA
,
Kirschmeier
P
, et al
.
A first-in-human, phase 1, dose-escalation study of dinaciclib, a novel cyclin-dependent kinase inhibitor, administered weekly in subjects with advanced malignancies
.
J Transl Med
.
2013
;
11
:
259
.
8.
Parry
D
,
Guzi
T
,
Shanahan
F
, et al
.
Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor
.
Mol Cancer Ther
.
2010
;
9
(
8
):
2344
-
2353
.
9.
Johnson
AJ
,
Yeh
YY
,
Smith
LL
, et al
.
The novel cyclin-dependent kinase inhibitor dinaciclib (SCH727965) promotes apoptosis and abrogates microenvironmental cytokine protection in chronic lymphocytic leukemia cells
.
Leukemia
.
2012
;
26
(
12
):
2554
-
2557
.
10.
Fu
W
,
Ma
L
,
Chu
B
, et al
.
The cyclin-dependent kinase inhibitor SCH 727965 (dinacliclib) induces the apoptosis of osteosarcoma cells
.
Mol Cancer Ther
.
2011
;
10
(
6
):
1018
-
1027
.
11.
Desai
BM
,
Villanueva
J
,
Nguyen
TT
, et al
.
The anti-melanoma activity of dinaciclib, a cyclin-dependent kinase inhibitor, is dependent on p53 signaling
.
PLoS One
.
2013
;
8
(
3
):
e59588
.
12.
Hussain
SR
,
Lucas
DM
,
Johnson
AJ
, et al
.
Flavopiridol causes early mitochondrial damage in chronic lymphocytic leukemia cells with impaired oxygen consumption and mobilization of intracellular calcium
.
Blood
.
2008
;
111
(
6
):
3190
-
3199
.
13.
Flynn
JM
,
Jones
JA
,
Andritsos
L
, et al
.
Update on the phase I study of the cyclin dependent kinase inhibitor dinaciclib (SCH 727965) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL): confirmation of clinical activity and feasibility of long-term administration [abstract]
.
Blood
.
2010
;
116
(
21
). Abstract 1396.
14.
Flynn
J
,
Jones
J
,
Johnson
AJ
, et al
.
Dinaciclib is a novel cyclin-dependent kinase inhibitor with significant clinical activity in relapsed and refractory chronic lymphocytic leukemia
.
Leukemia
.
2015
;
29
(
7
):
1524
-
1529
.
15.
Lemery
SJ
,
Zhang
J
,
Rothmann
MD
, et al
.
U.S. Food and Drug Administration approval: ofatumumab for the treatment of patients with chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab
.
Clin Cancer Res
.
2010
;
16
(
17
):
4331
-
4338
.
16.
GlaxoSmithKline
.
Arzerra (ofatumumab) [prescribing information]
. Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2009/125326lbl.pdf. Accessed 24 February 2016.
17.
Robak
T
.
Ofatumumab, a human monoclonal antibody for lymphoid malignancies and autoimmune disorders
.
Curr Opin Mol Ther
.
2008
;
10
(
3
):
294
-
309
.
18.
Coiffier
B
,
Lepretre
S
,
Pedersen
LM
, et al
.
Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1-2 study
.
Blood
.
2008
;
111
(
3
):
1094
-
1100
.
19.
Wierda
WG
,
Kipps
TJ
,
Mayer
J
, et al
;
Hx-CD20-406 Study Investigators
.
Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia
.
J Clin Oncol
.
2010
;
28
(
10
):
1749
-
1755
.
20.
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
.
21.
Hallek
M
,
Cheson
BD
,
Catovsky
D
, et al
;
International Workshop on Chronic Lymphocytic Leukemia
.
Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines
.
Blood
.
2008
;
111
(
12
):
5446
-
5456
.
22.
Stilgenbauer
S
,
Schnaiter
A
,
Paschka
P
, et al
.
Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial
.
Blood
.
2014
;
123
(
21
):
3247
-
3254
.
23.
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
.
24.
Byrd
JC
,
Lin
TS
,
Dalton
JT
, et al
.
Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia
.
Blood
.
2007
;
109
(
2
):
399
-
404
.
25.
Cairo
MS
,
Bishop
M
.
Tumour lysis syndrome: new therapeutic strategies and classification
.
Br J Haematol
.
2004
;
127
(
1
):
3
-
11
.

Author notes

*

P.G. and L.S. contributed equally to this study.