Chronic lymphocytic leukaemia with 17p deletion: a retrospective analysis of prognostic factors and...

Chronic lymphocytic leukaemia with 17p deletion:a retrospective analysis of prognostic factors and therapyresults

Chronic lymphocytic leukaemia (CLL) is the most common

leukaemia in Western countries, with an age-adjusted inci-

dence of about 3Æ8 new cases per 100 000 inhabitants per year

in Europe (Sant et al, 2010). The clinical course of the disease

is very heterogeneous and, while a significant proportion of

patients never require treatment, others have an aggressive

clinical course and experience early progression and death.

Recurrent chromosomal aberrations, as detected by interphase

fluorescence in-situ hybridization (FISH), have a reproducible

prognostic power in terms of response to therapy and also

treatment-free, progression-free and overall survival (OS)

(Dohner et al, 2000; Catovsky et al, 2007; Grever et al, 2007;

Hallek et al, 2010).

Patients with a 17p deletion (17p-) are considered to have a

very poor prognosis mainly due to their refractoriness to

conventional therapy (Hallek et al, 2010), and alternative more

Julio Delgado,1,2 Blanca Espinet,3 Ana C.

Oliveira,4 Pau Abrisqueta,5 Javier de la

Serna,6 Rosa Collado,7 Javier

Loscertales,8 Montserrat Lopez,9 Jose A.

Hernandez-Rivas,10 Christelle Ferra,11

Angel Ramirez,12 Josep M. Roncero,13

Cristina Lopez,1 Anna Aventin,2 Anna

Puiggros,3 Eugenia Abella,3 Felix

Carbonell,7 Dolors Costa,1 Anna Carrio1,

and Marcos Gonzalez14 on behalf of the

Grupo Espanol de Leucemia Linfatica

Cronica (GELLC) y Grupo Espanol de

Citogenetica Hematologica (GECGH)1Hospital Clinic, IDIBAPS, 2Hospital Sant Pau,3Hospital del Mar, 4Hospital Duran i Reynals,5Hospital Vall d’Hebron, Barcelona, 6Hospital 12

de Octubre, Madrid, 7Hospital General, Valencia,8Hospital La Princesa, 9Hospital Principe de

Asturias, 10Hospital Infanta Leonor, Madrid,11Hospital Germans Trias i Pujol, Badalona,12Hospital Central de Asturias, Oviedo, 13Hospital

Josep Trueta, Girona, and 14Hospital Clinico,

Salamanca, Spain

Received 4 November 2011; accepted for

publication 30 November 2011

Correspondence: Dr Julio Delgado, Department

of Haematology, Institute of Haematology and

Oncology, Hospital Clinic, IDIBAPS, University

of Barcelona, C/Villaroel 170, 08036 Barcelona,

Spain.

E-mail: [email protected]

Summary

Patients with chronic lymphocytic leukaemia (CLL) whose tumour cells

harbour a 17p deletion (17p-) are universally considered to have a poor

prognosis. The deletion can be detected at diagnosis or during the evolution

of the disease, particularly in patients who have received chemotherapy. We

sought to evaluate the natural history of patients with 17p- CLL, identify

predictive factors within this prognostic subgroup, and evaluate the results of

different therapeutic approaches. Data from 294 patients with 17p- CLL

followed up at 20 different institutions was retrospectively collected and

analysed. Median age was 68 (range 27–98) years at the time of fluorescence

in situ hybridization analysis. After 17p- documentation, 52% received

treatment, achieving an overall response rate of 50%. Median overall survival

was 41 months, and was significantly shorter in patients with elevated beta2-

microglobulin concentration (P < 0Æ001), B symptoms (P = 0Æ016), higher

percentage of cells with deletion (P < 0Æ001), and acquired deletions

(P = 0Æ012). These findings suggest that patients with 17p- CLL have a

variable prognosis that can be refined using simple clinical and laboratory

features, including 17p- clone size, beta2-microglobulin concentration,

presence of B symptoms and type of deletion (de novo versus acquired).

Keywords: 17p-, TP53, chronic lymphocytic leukaemia.

research paper

ª 2012 Blackwell Publishing Ltd First published online 9 January 2012British Journal of Haematology, 2012, 157, 67–74 doi:10.1111/j.1365-2141.2011.09000.x

effective but also more toxic therapeutic approaches, such as

alemtuzumab or allogeneic haematopoietic cell transplantation

(alloHCT), are generally recommended (Lozanski et al, 2004;

Dreger et al, 2007). The 17p deletion is found in 2–4% of cases

at diagnosis (de novo deletions), but can also be acquired

during the evolution of the disease, particularly in patients

who have received chemotherapy. Indeed, the incidence of

17p- in patients with relapsed or refractory CLL can be up to

30% (Stilgenbauer et al, 2009). However, the prognosis of

patients with 17p- is not always dismal because a proportion of

them may remain asymptomatic for prolonged periods of time

(Tam et al, 2009).

Large series of CLL patients with this genomic aberration are

lacking due to its low incidence. The aims of this study were:

(i) to analyse the natural history of patients with either de novo

or acquired 17p- CLL, (ii) to identify predictive factors within

this prognostic subgroup and (iii) to describe the results of

different therapeutic approaches.

Methods

Patient selection

Institutional databases were retrospectively screened for cases

with information available on the following variables: morpho-

logical and immunological diagnosis of CLL according to the

World Health Organization classification (Muller-Hermelink

et al, 2008), age, sex, Binet stage, absolute blood lymphocyte

count, presence of B symptoms, serum beta2-microglobulin

(B2M) concentration, date of FISH analysis, percentage of cells

with 17p-, time to treatment and type of CLL-specific therapy

(if required) and OS. All patients had interphase FISH tests

performed using probes specific for TP53 (17p13.1), ATM

(11q22.3), D13S319 (13q14.3) and the centromeric region of

chromosome 12 (12p11.1-q11). A proportion of patients also

had conventional cytogenetics (CC) results available. For the

purpose of this study, we considered deletions that were

documented at the time of CLL diagnosis as de novo, while

acquired deletions were those that were documented over the

course of the disease in patients who did not have a 17p deletion

at diagnosis. Patients who only had FISH tests performed after

therapy or more than 1 year after disease diagnosis were

considered to have undetermined deletions.

Analyses of CD38 and ZAP70 expression were performed

using conventional methods (Crespo et al, 2003). Of note, all

clinical and laboratory characteristics were recorded when the

17p- was documented, which was not necessarily the time of

CLL diagnosis. Standard criteria were used for both initiation

of therapy and response evaluation (Cheson et al, 1996).

Statistical analysis

Baseline characteristics and prognostic factors were compared

by using Chi-square or Fisher exact tests for discrete variables,

and the Mann–Whitney test for continuous variables. The

primary endpoint for comparison was OS. Kaplan–Meier

curves were plotted for this purpose and the effect of the

different variables assessed using the log-rank test. Variables

analysed were: age (<65 vs. ‡65 years), Binet stage (A–B versus

C), B symptoms (presence versus absence), absolute lymphocyte

count (<20 vs. ‡20 · 109/l), CD38 expression (positive versus

negative), ZAP70 expression (positive versus negative), B2M

(<2 vs. ‡2 times the upper limit of normal), type of deletion (de

novo versus acquired or undetermined) and percentage of cells

harbouring the 17p deletion, whose optimal cut-off point was

identified using receiver operating characteristic (ROC) curves.

Subsequently, multivariate analysis according to the Cox

proportional hazards regression model was used to explore

the independent effect of variables that showed a significant

influence on OS by univariate analysis. In the Cox regression

model, continuous variables (e.g. B2M, percentage of cells with

deletion, lymphocyte count) were not dichotomized.

For patients who received therapy after 17p- documenta-

tion, event-free survival (EFS) was calculated considering

disease progression requiring salvage therapy or death as

events. In this particular analysis, patients undergoing alloHCT

were censored at that point in time.

Generally, unadjusted two-sided P values <0Æ05 were con-

sidered significant, but in OS univariate studies, the statistical

significance cut-off was corrected according to the Bonferroni

method. As nine variables were analysed, only P values <0Æ005

were considered significant. All statistical analyses were per-

formed using spss, version 18 (IBM, Armonk, NY, USA).

Results

Baseline characteristics

The characteristics of the study population are shown in

Table I. We identified 147 (50%) patients with de novo and 67

(23%) patients with acquired 17p- (i.e. not present at diagnosis

of CLL). In 80 (27%) patients, FISH results were only available

at progression or after therapy and they were considered to

have an undetermined 17p- status. As patients with acquired

and undetermined 17p- had a similar outcome (see below),

they were grouped together for the purpose of this study. In

general, patients with acquired or undetermined 17p- had

more advanced disease, as suggested by a higher Binet stage,

lower IgG levels and a trend towards a higher B2M concen-

tration (Table I).

Median age was 68 years (range, 27–98 years) at the time of

FISH analysis. Binet stage was A or B in 236 patients (80%)

and C in 51 patients (18%). Furthermore, 69 (25%) patients

presented with B symptoms and 99 (35%) had a lymphocyte

count higher than 50 · 109/l. Results of CD38 and ZAP70

expression were available in 83% and 68% of patients

(Table I). Data on IGHV mutation status was only available

in 32% of patients and was, therefore, not evaluated. Median

follow-up was 18 months (range, 1–130) from FISH analysis

and 58 months (range, 1–313) from CLL diagnosis.

J. Delgado et al

68 ª 2012 Blackwell Publishing LtdBritish Journal of Haematology, 2012, 157, 67–74

FISH and cytogenetics

The use of mitogens, number of nuclei analysed and cut-off

points varied across the different institutions. FISH tests were

performed on unstimulated peripheral blood cells in 153

patients (52%), while mitogens were used in the remaining 141

patients (47%). Tetradecanoylphorbol acetate (TPA) was the

mitogen chosen in 140 cases, and only one patients’ cells were

stimulated with interleukin-2+ DSP30. The number of cells

analysed was at least 200 in the majority of cases (97%) and

only 3% of patients had their tests performed in 100 cells. Cut-

off points for positivity were 10% in 76% of cases, 7% in 8% of

cases, and 5% in 16% of cases. Of note, the use of mitogens

had no significant influence on the percentage of positive cells

(data not shown).

Apart from the 17p deletion, 13q deletion was identified in

50% of patients, trisomy 12 in 17% and 11q deletion in 11%.

Conventional cytogenetics was also available in 124 (42%) of

cases, and 50 of them (40%) were considered to have a

complex karyotype according to standard criteria (Haferlach

et al, 2010).

Therapy

Therapy was administered to 210 patients (71%) at a median

of 12 months after diagnosis of CLL (range, 0–167 months). In

patients with de novo deletions the median time to first

treatment was significantly determined by the clone size (50 vs.

7 months for patients with <25% and ‡25% cells with

17p-, respectively, P = 0Æ016). In patients with acquired or

undetermined deletions, the median number or therapies prior

to 17p- documentation was 1 (range 0–6), and 30 of these

patients (27%) acquired the deletion spontaneously (i.e.

without any treatment) at a median of 49 months from CLL

diagnosis (range 4–120 months).

After the 17p- documentation, 156 patients received

treatment (Table II). The most frequently used therapies

were chlorambucil (17%), fludarabine + cyclophosphamide

(±mitoxantrone) (20%), rituximab + fludarabine + cyclo-

phosphamide (±mitoxantrone) (17%), rituximab + chemo-

therapy not including fludarabine (22%), chemotherapy not

including fludarabine (7%) and alemtuzumab (12%).

Response to therapy was clearly documented in 144 patients,

and the overall response rate was 50%. Table II shows the

response rate and EFS of the different therapies stratified

according to the size of the 17p- clone. In general, there was a

tendency towards a lower response rate, and also shorter EFS, in

patients with more than 25% cells harbouring a 17p deletion.

Overall survival

Median OS from FISH analysis was 41 months for the entire

cohort, being significantly longer in patients with de novo 17p-

(62 months) compared to patients with acquired (34 months)

or undetermined deletions (36 months) (P = 0Æ001). Table III

and Fig 1 show other variables significantly associated with a

significantly prolonged OS: Binet stage A or B (P = 0Æ001),

absence of B symptoms (P < 0Æ001), B2M concentration lower

than 2 times the upper limit of normal (P < 0Æ001) and <25%

of cells with deletion (P < 0Æ001). Of note, the percentage of

cells with deletion was significant at almost any cut-off point

tested. Indeed, the median OS of patients with <25%, 25–74%

and >75% 17p- cells was 64, 39 and 21 months, respectively

Table I. Baseline characteristics at the time of 17p- detection.

De novo (N = 147)

Acquired or

undetermined

(N = 147) P value

Age at FISH analysis (years), median (range) 69 (40–98) 68 (27–87) 0Æ23

Age at CLL diagnosis (years), median (range) 67 (40–98) 60 (24–84) <0Æ001

Binet stage C, N (%) 15 (10) 36 (25) 0Æ001

Presence of B symptoms, N (%) 32 (23) 37 (27) 0Æ49

Absolute lymphocyte count (·109/L), median (range) 16Æ9 (1Æ0–446) 29Æ5 (0Æ7–219) 0Æ33

Serum beta2-microglobulin (mg/l), median (range) 2Æ8 (0Æ6–9Æ82) 3Æ5 (0Æ5–21Æ5) 0Æ09

Serum IgG concentration (g/l), median (range) 8Æ9 (1Æ8–27Æ6) 7Æ9 (1Æ3–21Æ7) 0Æ008

Positive CD38 expression, N (%) 40 (32) 54 (45) 0Æ05

Positive ZAP-70 expression, N (%) 43 (41) 46 (48) 0Æ32

Percentage of cells with 17p deletion, median (range) 41 (5–100) 30 (5–100) 0Æ21

Additional cytogenetic aberrations

13q deletion 80 (56) 63 (44) 0Æ08

Trisomy 12 23 (16) 26 (18) 0Æ64

11q deletion 17 (12) 14 (10) 0Æ70

Complex karyotype (patients with CC only) 26 (41) 24 (39) 0Æ86

Follow-up from FISH analysis (months), median (range) 20 (1–118) 14 (1–104) 0Æ002

Follow-up from CLL diagnosis (months), median (range) 27 (1–147) 89 (12–324) <0Æ001

FISH, fluorescence in situ hybridization; CLL, chronic lymphocytic leukaemia; CC, conventional cytogenetics.

17p- CLL

ª 2012 Blackwell Publishing Ltd 69British Journal of Haematology, 2012, 157, 67–74

(P < 0Æ001). However, ROC analysis revealed that 25% was the

optimal cut-off point for this variable, as it was able to predict

the 3-year-OS with 77% sensitivity and 60% specificity.

Interestingly, patients with a complex karyotype did not have

a significantly worse median OS compared to those with

isolated 17p deletion (40 vs. 62 months, respectively,

P = 0Æ147).

Cox regression analysis revealed four variables with inde-

pendent prognostic value at the time of 17p- documentation:

B2M concentration (P < 0Æ001), B symptoms (P = 0Æ016),

percentage of cells with deletion (P < 0Æ001) and de novo

deletions (P = 0Æ012).

Patients with stage A disease and de novo 17p deletions

Eighty-eight patients from our cohort presented with stage A

disease and de novo 17p deletions. By definition, all were

previously untreated at the time of FISH analysis, but 34

patients (39%) have subsequently required therapy at a median

follow-up of 21 months (range 9–118). The overall response

rate in these patients requiring therapy was 50% (25%

complete responses), the 3-year EFS was 30% [95% confidence

interval (CI) 10–50%] and the 3-year-OS was 57% (37–77%).

In contrast, the 3-year OS of patients who did not require

therapy was 85% (73–97%). Multivariate analysis revealed that

factors associated with a shorter OS in this subgroup of

patients were B2M [hazard ratio (HR) 1Æ55; 95% CI 1Æ14–2Æ09;

P = 0Æ005] and percentage of cells with deletion (HR 1Æ03; 95%

CI 1Æ01–1Æ06; P = 0Æ002). Once again, 25% was the best cut-off

point for the percentage of 17p- cells, and two times the upper

limit of normal was the best cut-off point for B2M. When these

factors were combined in a simple prognostic index, patients

with zero, one and two of these factors had a 3-year-OS of

94%, 83% and 14%, respectively.

Table III. Univariate and multivariate analysis of variables with a significant impact on overall survival.

Univariate Multivariate

Median OS

(95% CI)

in months

P value

(log rank

test)

Hazard ratio

(95% CI)

P value

(Cox

regression)

Binet stage A-B 46 (26–67) P = 0Æ001

C 23 (4–43)

B symptoms Yes 21 (10–32) P < 0Æ001 1Æ78 (1Æ11–2Æ83) P = 0Æ016

No 41 (30–53)

Beta2-microglobulin (times the upper limit

of normal)

<2 134 (NC) P < 0Æ001 1Æ15 (1Æ09–1Æ21) P < 0Æ001

‡2 27 (17–36)

Percentage of cells with 17p deletion (%) <25 64 (60–67) P = 0Æ001 1Æ01 (1Æ01–1Æ02) P < 0Æ001

‡25 35 (29–40)

Type of deletion De novo 62 (21–103) P = 0Æ001 1Æ77 (1Æ14–2Æ76) P = 0Æ012

Acquired or undetermined 35 (27–43)

OS, overall survival; CI, confidence interval; NC, not calculated.

Table II. Response to the first treatment administered after the 17p- detection in the 144 patients for whom response rates were clearly documented.

N

Overall response (complete

response)Median EFS

(95% CI)

(months)

<25% of 17p-

cells (%)

‡25% of 17p-

cells (%)

Chlorambucil 25 25% (0) 12% (6) 6Æ1 (3Æ1–9Æ0)

Fludarabine + cyclophosphamide (±mitoxantrone) 30 72% (14) 50% (19) 12Æ3 (7Æ8–16Æ8)

Rituximab + fludarabine + cyclophosphamide (±mitoxantrone) 23 91% (55) 75% (42) 31 (0–62Æ4)

Rituximab + chemotherapy not including fludarabine (e.g. R-CHOP) 31 50% (12) 57% (0) 7Æ1 (4Æ2–10)

Chemotherapy not including fludarabine (e.g. CHOP) 7 0% (0) 0% (0) 4Æ5 (0–9)

Alemtuzumab 20 50% (0) 56% (19) 27Æ6 (3Æ8–51Æ4)

Glucocorticoids 3 – 67% (0) 4Æ7 (NC)

Other 6 0% (0) 50% (0) 5Æ3 (1Æ6–9Æ1)

CR, complete response; PR, partial response; EFS, event-free survival; CI, confidence interval; R-CHOP, rituximab + cyclophosphamide + adria-

mycin + vincristine + prednisone; CHOP, cyclophosphamide + adriamycin + vincristine + prednisone; NC, not calculated.

J. Delgado et al


Discussion

The concept that 17p deletion conveys poor prognosis in

patients with CLL mainly derives from studies of subjects

included in clinical trials because of active disease, and hence

with poor prognosis. In fact, the incidence of 17p deletion in

patients included in clinical trials (6–8%) (Catovsky et al,

2007; Hallek et al, 2010; Robak et al, 2010) is higher than that

found in unselected series of patients studied at diagnosis (2–

4%) (Shanafelt et al, 2006; Stilgenbauer et al, 2007). In line

with this, acquired 17p- CLL has been associated with a shorter

survival compared to de novo 17p- CLL (Shanafelt et al, 2006,

2008; Stilgenbauer et al, 2007). In order to clarify these issues

and further refine the prognosis of these patients, we

retrospectively collected clinical and laboratory data from

294 patients with 17p- CLL treated at 20 different institutions.

As the main objective of this study was to guide clinicians

looking after these patients, all variables were recorded at the

Months144120967248240

Ove

rall

surv

ival

1·0

0·8

0·6

0·4

0·2

0·0

C-censoredA-B-censoredCA-B

Binet Stage(A)

Months144120967248240

1·0

0·8

0·6

0·4

0·2

0·0

Yes-censoredNo-censoredYesNo

B symptoms(B)

Months144120967248240

1·0

0·8

0·6

0·4

0·2

0·0

>2xULN-censored<2xULN-censored>2xULN<2xULNB2M(C)

Months144120967248240

1·0

0·8

0·6

0·4

0·2

0·0

>20%-censored<20%-censored>20%<20%

% of 17p- cells(D)

Months144120967248240

1·0

0·8

0·6

0·4

0·2

0·0

De Novo-censoredOther-censoredDe novoOther

Type of deletion(E)

Ove

rall

surv

ival

Ove

rall

surv

ival

Ove

rall

surv

ival

Ove

rall

surv

ival

Fig 1. Overall survival according to (A) Binet stage A or B versus C (P = 0Æ001); (B) presence or absence of B symptoms (P < 0Æ001); (C) beta2-

microglobulin (B2M) concentration [<2 vs. ‡2 times the upper limit of normal (ULN); P < 0Æ001]; (D) percentage of cells with 17p deletion (<25 vs.

‡25%; P < 0Æ001); and (E) type of deletion (de novo versus acquired or undetermined; P = 0Æ001).

17p- CLL


time of 17p- documentation, which is when difficult decisions

have to be made, including what treatment, if any, should the

patient receive, or whether a donor search should be initiated

or not.

As in other series, we identified a group of patients (44%)

with de novo 17p deletion whose disease had not required any

intervention at a median of 19 months from FISH detection

(Best et al, 2009; Tam et al, 2009). On the other hand, patients

with acquired or undetermined 17p- had a significantly shorter

3-year OS (47%) compared to patients with de novo

17p- (64%), which was almost identical to that reported by

Tam et al (2009) (65%). These results are in keeping with

previously published series (Shanafelt et al, 2006, 2008;

Stilgenbauer et al, 2007), although they may simply reflect

that patients with acquired deletions had a more advanced

disease and could have received one or more lines of therapy at

the time the genetic aberration was detected.

We have confirmed the importance of the clone size, not

only using a 25% cut-off level, but also as a continuous

variable. There has been some controversy in the past

regarding the optimal cut-off point for 17p deletion. Initial

studies (Dohner et al, 1995) considered 3% as a valid cut-off

level, while Catovsky et al (2007) showed that only patients

with more than 20% 17p- cells had a significantly inferior

outcome among those recruited to the CLL4 trial. However,

these initial results were not confirmed in a subsequent

analysis of the same CLL4 cohort, and the cut-off was finally

set at 10% (Oscier et al, 2010). In our series, 25% was the

optimal cut-off point, which is in keeping with previously

published data (Tam et al, 2009).

Moreover, we found that B2M had a greater predictive value

despite the multicentre nature of this study and the different

normal range of each institution. Patients with a B2M

concentration lower than 2 times the upper normal limit had

a median OS of 134 months, which was five times longer than

that of patients with a higher B2M (27 months). This is not

surprising as many studies have confirmed the prognostic

value of B2M in patients with CLL (Delgado et al, 2009;

Wierda et al, 2009).

In contrast to recently published randomized trials (Catov-

sky et al, 2007; Grever et al, 2007), fludarabine-based combi-

nations were reasonably efficacious in patients with 17p

deletion, particularly when rituximab was part of the treat-

ment. The response rate, however, was slightly inferior in

patients with 17p- clones >25% [overall response rate (ORR):

75% vs. 91%; median EFS: 18 vs. 38 months], but still

comparable to the responses achieved with alemtuzumab.

These results are in line with those reported by Tam et al

(2009) and also the German CLL8 trial, where 17p- patients

receiving rituximab, fludarabine and cyclophosphamide had a

significantly better response rate compared to those who

received fludarabine and cyclophosphamide (68% vs. 34%,

P = 0Æ025) (Hallek et al, 2010). This, however, is not meant as

a comparative analysis, as the different therapeutic approaches

were not assigned randomly and also because it is impossible

to draw meaningful conclusions without controlling for

disease status, patient demographics, etc. On the other hand,

even though chemoimmunotherapy was effective in a signif-

icant number of patients, the proportion of them achieving a

complete remission with negative minimal residual disease was

quite small, highlighting the need for new therapeutic agents

for patients with 17p- CLL.

Younger and fitter patients with 17p- CLL requiring

treatment are considered candidates for allogeneic transplan-

tation in view of their poor outcome and the absence of

alternative curative approaches (Dreger et al, 2007). A retro-

spective analysis revealed a 3-year OS of 44% in patients with

17p- CLL undergoing allogeneic transplantation, with a

significant number of patients being alive and disease free 4–

8 years after the procedure (Schetelig et al, 2008); and a recent

prospective trial from the German Group revealed even better

results in this subgroup of patients (59% at 4 years) (Dreger

et al, 2010). In our series, patients with de novo deletions, stage

A disease, low percentage of 17p- cells and low B2M were

unlikely to require therapy in the near future (17% at 3 years),

have a favourable outcome (OS >90% at 3 years) and it is

unclear whether they would benefit from alloHCT. However, if

the disease requires therapy, only 30% of patients have a

response lasting more than 3 years and OS drops significantly

to 57%. Consequently, patients with 17p- CLL requiring

therapy should be referred for alloHCT, even if they present

with de novo deletions and stage A disease.

It has been recently shown that TP53 mutations have an

important negative impact on patients’ outcome (Zenz et al,

2010; Gonzalez et al, 2011). These mutations are usually

present in the non-deleted allele of patients with 17p- CLL

and occur in approximately 5% of patients. Unfortunately, in

our series TP53 sequencing analysis was only available in a

small proportion of patients, this precluding a meaningful

analysis.

In conclusion, the prognosis of patients with 17p- CLL can

be refined by simple and widely available clinical and

laboratory features. Patients with de novo deletions, stage A

disease, low percentage of 17p- cells and low B2M should be

reassured as they are unlikely to require therapy and have a

favourable outcome. In contrast, patients requiring therapy

have a significantly worse outcome and should be referred for

alloHCT. Regarding the therapeutic approach for 17p- CLL

patients, none can be considered satisfactory. Because of this,

patients should be recruited, whenever possible, in clinical

trials exploring not only new cytotoxic agents but also cellular

therapy and immunomodulation.

Acknowledgements

The following investigators also contributed clinical or labo-

ratory data to this study: Javier Grau (Hospital Germans Trias i

Pujol, Badalona); Eva Gimeno (Hospital del Mar, Barcelona);

Maria Jose Marco (Hospital General, Castellon); Ismael Buno

(Hospital Gregorio Maranon, Madrid); Eva Arranz (Hospital

J. Delgado et al


La Princesa, Madrid); Inmaculada Perez (Hospital Virgen de la

Victoria, Malaga); Elisa Luno (Hospital Central de Asturias,

Oviedo); Jesus M. Hernandez-Rivas (Hospital Clinico, Salam-

anca); Teresa Gonzalez (Fundacion Galega de Medicina

Xenomica, Santiago); Isabel Marugan (Hospital Clinic, Valen-

cia); Jose Cervera (Hospital La Fe, Valencia). We are grateful to

Prof. Emili Montserrat for critically reading the manuscript.

This work has been performed thanks in part to Red

Tematica de Investigacion Cooperativa en Cancer grant RT

06/0020/002051 Spanish Ministry of Science, Instituto Carlos

III FISS PI080304, and Generalitat de Catalunya

2009SGR1008.

Author contributions

JD designed the research study, provided patient data, analysed

the data and wrote the paper. BE, ACO, PA, JS, RC, JL, ML,

JAHR, CF, AR, JMR, CL, AA, AP, EA, FC, DC, AC y MG

provided patient data. All authors read the last version of the

manuscript.

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Chronic lymphocytic leukaemia with 17p deletion: a retrospective analysis of prognostic factors and...

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