Abstract

Introduction. CLL primarily affects elderly individuals who frequently have comorbid health conditions. It is typically assumed non-CLL-related etiologies will be the ultimate cause of death for most CLL patients, particularly those with comorbid conditions at diagnosis.

Methods. Between 9/2002 and 11/2014, 1174 patients with newly diagnosed CLL were enrolled in a prospective cohort study evaluating the natural history of CLL. Comorbidities were prospectively recorded at the time of diagnosis. Comorbidities arising during the course of disease were not considered for this analysis. Standardized longitudinal follow-up was performed in all patients every 6 months for the first 3 years after diagnosis and annually thereafter through 04/2015. Internal and external medical records, death certificates, and information from next of kin were centrally reviewed to determine cause of death, using a standardized protocol. Categorical and continuous variables were evaluated using the c2 or Fisher exact tests and the Mann-Whitney test, as appropriate.

Results. Baseline characteristics at time of CLL diagnosis are shown in the Table. Over 80% of patients had 2 or more comorbidities at diagnosis (median 3, range 0-11). After a median follow up of 5 years, 224 (19%) patients have died. The cause of death could be accurately determined in 183 (82%) of these patients. The cause of death was due to CLL in 135 (74%), including 84 (46%) CLL progressions, 14 (8%) infections, and 37 (20%) other cancers. Death was due to non-CLL-related causes (such as congestive heart failure, stroke or chronic obstructive pulmonary disease) in the remaining 48 (26%) patients. On univariable analysis, age and number of comorbid health conditions were not related to whether or not the cause of death was related/unrelated to CLL. The only specific co-morbid condition at diagnosis that predicted for non-CLL related death was stroke (8% vs 1%, p=0.04). Unmutated IGHV was the only prognostic factor thatpredicted greater likelihood of CLL-related death (70% vs 50%, p=0.03).

Conclusions. The majority of patients with CLL have multiple comorbidities at time of diagnosis. Despite this fact, CLL progression and/or CLL-related complications are the primary cause of death. The number and type of comorbidities at diagnosis have minimal relationship to whether or not the ultimate cause of death was CLL-related. In contrast, the CLL-specific characteristic IGHV status (but interestingly not FISH defects) correlates with cause of death. Collectively, these findings illustrate the need for more effective CLL therapy, particularly treatments that can be tolerated by patients with comorbid health conditions. It is hoped the signaling inhibitors may help address this unmet need.

Table.
Number (%), median [range]
N=1174
Age (years) 63 [23-89] 
Males
Females 
791 (67)
383 (33) 
Creatinine-Clearance > (mL/min) 86 [10-252] 
B2M (mg/dL) 2.3 [1.1-13.2] 
Rai stage 0
I-II
III-IV 
604 (52)
512 (38)
54 (10) 
CD49d positive
negative 
277 (30)
638 (70) 
CD38 positive
negative 
332 (30)
780 (70) 
ZAP70 positive
negative 
380 (37)
650 (63) 
IGHV unmutated
mutated 
394 (44)
506 (56) 
FISH del13q
negative
+12
del11q
del17p 
395 (40)
175 (18)
276 (28)
90 (9)
50 (5) 
Comorbid health conditions  
Other cancers 237 (20) 
Stroke 38 (3) 
Cardiac disease 326 (28) 
Hypertension 472 (40) 
Respiratory 210 (18) 
Endocrinologic 165 (14) 
Diabetes 118 (10) 
Hyperlipidemia 485 (41) 
Rheumatologic 489 (42) 
Gastrointestinal 384 (33) 
Genitourinary 412 (35) 
Psychiatric 197 (17) 
DVT/PE 33 (3) 
Substance abuse 58 (5) 
Sexually transmitted disease 35 (3) 
Obesity 376 (32) 
# of Comorbidities 0
1
2
3
4
> 4 
66 (6)
148 (13)
203 (17)
220 (19)
206 (17)
331 (28) 
Number (%), median [range]
N=1174
Age (years) 63 [23-89] 
Males
Females 
791 (67)
383 (33) 
Creatinine-Clearance > (mL/min) 86 [10-252] 
B2M (mg/dL) 2.3 [1.1-13.2] 
Rai stage 0
I-II
III-IV 
604 (52)
512 (38)
54 (10) 
CD49d positive
negative 
277 (30)
638 (70) 
CD38 positive
negative 
332 (30)
780 (70) 
ZAP70 positive
negative 
380 (37)
650 (63) 
IGHV unmutated
mutated 
394 (44)
506 (56) 
FISH del13q
negative
+12
del11q
del17p 
395 (40)
175 (18)
276 (28)
90 (9)
50 (5) 
Comorbid health conditions  
Other cancers 237 (20) 
Stroke 38 (3) 
Cardiac disease 326 (28) 
Hypertension 472 (40) 
Respiratory 210 (18) 
Endocrinologic 165 (14) 
Diabetes 118 (10) 
Hyperlipidemia 485 (41) 
Rheumatologic 489 (42) 
Gastrointestinal 384 (33) 
Genitourinary 412 (35) 
Psychiatric 197 (17) 
DVT/PE 33 (3) 
Substance abuse 58 (5) 
Sexually transmitted disease 35 (3) 
Obesity 376 (32) 
# of Comorbidities 0
1
2
3
4
> 4 
66 (6)
148 (13)
203 (17)
220 (19)
206 (17)
331 (28) 

Disclosures

Kay:Hospira: Research Funding; Genentech: Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Tolero Pharma: Research Funding. Cerhan:Kite Pharma: Research Funding.

Author notes

*

Asterisk with author names denotes non-ASH members.