IGHV mutational status and FISH cytogenetics

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Jan 17, 2017 - ferent risk groups: (1) low-risk (mutated IGHV1 no adverse FISH cytogenetics [del(17p), del(11q)]);. (2) intermediate-risk (either unmutated IGHV ...
Received: 10 January 2017

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Revised: 17 January 2017

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Accepted: 20 January 2017

DOI 10.1002/ajh.24660

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RESEARCH ARTICLE

Chronic lymphocytic leukemia: A prognostic model comprising only two biomarkers (IGHV mutational status and FISH cytogenetics) separates patients with different outcome and simplifies the CLL-IPI Julio Delgado1 | Michael Doubek2,3 | Tycho Baumann1 | Jana Kotaskova2,3 | Stefano Molica4 | Pablo Mozas1 | Alfredo Rivas-Delgado1 | Fortunato Morabito5 | Sarka Pospisilova2,3 | Emili Montserrat1 1

Department of Hematology, Institute of Hematology and Oncology, Hospital Clínic, IDIBAPS, University of Barcelona, Barcelona, Spain; 2Department of Internal Medicine – Hematology and Oncology, University Hospital Brno and Medical Faculty, Brno, Czech Republic; 3Central European Institute of Technology (CEITEC), Masaryk University, Brno, Czech Republic; 4Department Hematology-Oncology, Azienda Ospedaliera Pugliese-Ciaccio, Catanzaro, Italy; 5UOC Ematologia, Azienda Ospedaliera di Cosenza, Cosenza, Italy Correspondence Emili Montserrat, Department of Hematology, Institute of Hematology and Oncology, Hospital Clinic, University of Barcelona, Villarroel, 170, 08036 Barcelona, Spain. Email: [email protected] Funding information n Cooperativa Red Tematica de Investigacio en Cancer RT, Grant/Award Numbers: 06/ 0020/002051 and RD12/0036/0023; Instituto de Salud Carlos III (ISCIII), Grant/ Award Number: FISS PI080304; ICGC-CLL Genome Project, Generalitat de Catalunya, Grant/Award Numbers: 2009SGR1008; “Emili Letang” (T.B.); Ministry of Health of the Czech Republic (The Czech team), Grant/Award Numbers: AZV 15-31834A/ 2015 and AZV 15-30015A/2015; Ministry of Education, Youth and Sports of the Czech Republic project NPUII - CEITEC 2020, Grant/Award Number: LQ1601.

Abstract Rai and Binet staging systems are important to predict the outcome of patients with chronic lymphocytic leukemia (CLL) but do not reflect the biologic diversity of the disease nor predict response to therapy, which ultimately shape patients’ outcome. We devised a biomarkers-only CLL prognostic system based on the two most important prognostic parameters in CLL (i.e., IGHV mutational status and fluorescence in situ hybridization [FISH] cytogenetics), separating three different risk groups: (1) low-risk (mutated IGHV 1 no adverse FISH cytogenetics [del(17p), del(11q)]); (2) intermediate-risk (either unmutated IGHV or adverse FISH cytogenetics) and (3) high-risk (unmutated IGHV 1 adverse FISH cytogenetics). In 524 unselected subjects with CLL, the 10-year overall survival was 82% (95% CI 76%-88%), 52% (45%-62%), and 27% (17%-42%) for the low-, intermediate-, and high-risk groups, respectively. Patients with low-risk comprised around 50% of the series and had a life expectancy comparable to the general population. The prognostic model was fully validated in two independent cohorts, including 417 patients representative of general CLL population and 337 patients with Binet stage A CLL. The model had a similar discriminatory value as the CLL-IPI. Moreover, it applied to all patients with CLL independently of age, and separated patients with different risk within Rai or Binet clinical stages. The biomarkers-only CLL prognostic system presented here simplifies the CLL-IPI and could be useful in daily practice and to stratify patients in clinical trials.

1 | INTRODUCTION

sues, heterogeneous biology and variable clinical course. While the median overall survival (OS) of patients with CLL is around 12 years,

Chronic lymphocytic leukemia (CLL) is characterised by the accumula-

the prognosis of individual patients ranges from a few years to a nor-

tion of monoclonal CD51 B cells with a typical phenotype (i.e., CD191,

mal lifespan.1 Clinical staging systems2,3 are used to stratify patients

CD20weak, CD231) in bone marrow, peripheral blood, and lymphoid tis-

with CLL. However, in Western countries around 80% of patients with

Am J Hematol. 2017;92:375–380

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CLL are currently diagnosed in early (Rai stage 0 or Binet stage A) clinical stage, this limiting the prognostic significance of clinical stages as a

T A B LE 1

ET AL.

Baseline characteristics of the Barcelona series

Characteristic

N 5 524

of CLL that accounts for its clinical heterogeneity1 and do not predict

Age in years, median (range)

62 (22-93)

response to therapy which is the most important predictor of

Sex, %M/%F

60/40

Binet stage B or C, n (%)

89 (17)

Rai stage I-IV, n (%)

198 (38)

Unmutated IGHV genes, n (%)

300 (57)

Adverse genomic aberrations (FISH) 11q deletion, n (%) 17p deletion, n (%)

66 (13) 23 (4)

groups (i.e., low-, intermediate-, high-, and very-high), of which the

Complex karyotype (> anomalies)

31/397 (8)

very high-risk group is very small, altogether complicating its applicabil-

Beta2-microglobulin, median (range)

2.2 (0.2-16.5)

ity. The aim of this study was to simplify the CLL-IPI.

Abnormal LDH serum concentration, n (%)

54/510 (11)

CLL-IPI using Rai staging system Low risk, n (%) Intermediate risk, n (%) High risk, n (%) Very high risk, n (%)

241 (46) 178 (34) 91 (17) 14 (3)

CLL-IPI using Binet staging system Low risk, n (%) Intermediate risk, n (%) High risk, n (%) Very high risk, n (%)

256 (49) 180 (34) 79 (15) 9 (2)

shop on CLL.11 FISH studies for del(11q), del(13q), and del(17p) and

ZAP70 >20% n (%)

178/501 (36)

trisomy 12 were performed using the Vysis CLL probe kit (Abbott, Des

CD38 >30% n (%)

143/467 (31)

CD49d >20% n (%)

124/317 (39)

TP53 mutations, n (%)

12/409 (3)

Brno Hospital, Czech Republic and 337 newly diagnosed patients with

ATM mutations, n (%)

27/359 (8)

stage A disease from several Italian institutions prospectively enrolled

NOTCH1 mutations, n (%)

48/452 (11)

SF3B1 mutations, n (%)

40/422 (9)

Patients treated, n (%)

292 (56)

diagnosis to the date of death or last follow-up. Relative survival was

First-line therapy (n 5 292) FCR or similar Purine analogs w/o MoAbs Alkylating agents Others

83 82 86 23

defined as the ratio between the observed actuarial survival and the

Follow-up in years, median (range)

8.3 (0.1-38)

whole.4 In addition, clinical stages do not reflect the complex biology

5,6

survival.

Recently, a prognostic index called CLL International Prognostic Index (CLL-IPI), based on the assessment of five variables (i.e., age, beta2 microglobulin, IGHV mutational status, del17p and clinical stage), has been proposed and validated.7–10 Of note, the CLL-IPI includes continuous parameters (i.e., age, serum beta-2 microglobulin), gives different weight to the included variables, and separates four prognostic

2 | METHODS From the database of the Department of Hematology, Hospital Clinic Barcelona, we retrieved 524 patients in whom information at diagnosis included age, clinical stage (Rai and Binet), IGHV mutational status, beta2-microglobulin (B2M), and fluorescence in situ hybridization (FISH)-detected cytogenetic abnormalities. Diagnosis and criteria for starting therapy were those recommended by the International Work-

Plaines, IL). IGHV-IGHD-IGHJ rearrangements and mutational status were analysed according to ERIC recommendations.12 For validation purposes, we used a cohort of 417 patients from the University of

into

the

OCLL1-GISL

protocol

(clinicaltrial.govidentifier:

115

NCT00917540). The study was reviewed and approved by the Institutional Review Boards. Primary endpoints were time to first treatment (TTFT) and OS. TTFT was calculated from the date of diagnosis to the date of first treatment or last follow-up, considering disease-unrelated deaths as competing events.13 OS was calculated from the date of

expected survival derived from a subset of the Spanish and Czech population (as appropriate) matched by age, sex, and calendar year of diagnosis (relsurv package). The internal validity of each model was evaluated using bootstrapping, and the discriminatory value of each

(30%) (30%) (31%) (9%)

Abbreviations: IGHV, variable region of the immunoglobulin heavy chain gene; FISH, fluorescent in situ hybridization; CLL-IPI, chronic lymphocytic leukemia international prognostic index; FCR, fludarabine, cyclophosphamide and rituximab; MoAbs, monoclonal antibodies.

regression model was estimated using c-statistics (rms package). All calculations were performed using R, version 3.2.2. Double sided P values < .05 were considered significant.

prognostic value in terms of OS. In our hands, both sets of variables (i. e., age 1 B2M 1 IGHV 1 FISH 1 Rai; or age 1 B2M 1 IGHV 1 FISH 1

3 | RESULTS

Binet) confirmed their independent prognostic value (Supporting Information Table I). Moreover, all CLL-IPI four patient subgroups had a sig-

The main characteristics of the training (Barcelona) series are shown in

nificantly different survival, although the high- and very-high risk

Table 1. First, we performed multivariable analyses to confirm that in

groups overlapped, and as in the original description of the CLL-IPI and

our series all five covariates included in the CLL-IPI had independent

in external validation series the number of patients in the very high-risk

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F I G U R E 1 Time to first therapy (A) and OS (B) of the training (Barcelona) series according to the biomarkers-only model. Relative survival (C) of the training (Barcelona) series according to the biomarkers-only model with regard to Spanish population. Treatment-free survival (D) of the second validation stage A disease, Italian cohort according to the biomarkers-only model. OS of the training (Barcelona) series according to the biomarkers-only modelbut stratified by age (younger [E] and older [F] than 65 years at diagnosis). The same color code has been used in all panels: black for low, red for intermediate and green for high risk disease with the exception of panel 1D, were blue, green and red were used for the low, intermediate and high risk groups, respectively. [Color figure can be viewed at wileyonlinelibrary.com]

subgroup was quite low (2-3% in the Barcelona series) (Supporting

Compared with the training (Barcelona) cohort, the validation (Brno) series (n 5 417) presented with similar age and sex distribution

Information Figure 1). Next, we identified combinations of biomarkers with significant

but poorer clinical and biological features, including a larger proportion

mutational

of patients with unmutated IGHV (64% vs. 43%) and poor FISH cytoge-

status 1 FISH-detected genetic aberrations (i.e., del17p, del11q) was

netics (27% vs. 17%) (Supporting Information Table II). Also, patients

found to be able to segregate patients with different TTFT and OS.

from the Brno series received chemoimmunotherapy more frequently

Thus, in 524 unselected subjects with CLL from the Barcelona group,

than those from the training series (45% vs.30%) as initial therapy. All

TTFT at 5-years was 22% (95% CI:18–28%), 63% (55–70%) and 82%

these differences notwithstanding, the two-biomarker prognostic

discriminatory

value.

The

combination

of

IGHV

(69–90%) for patients in the low-, intermediate-, and high-risk groups,

model was fully validated in the Brno series both in terms of TTFT and

respectively. And 10-year overall survival was 82% (76–88%), 52%

OS (Supporting Information Figure 2). We finally evaluated the

(45–62%), and 27% (17–42%) for the low-, intermediate-, and high-

biomarkers-only CLL prognostic model in the context of the Spanish

risk groups, respectively (Figure 1A,B) (c-statistic: 0.68). Likewise, in an

and Czech general population, as appropriate. The model separated

analysis restricted to 337 patients with stage A disease from different

patients with markedly different relative survivals (HR 3.7; 95% CI:

Italian institutions, the TTFF for patients in low-, intermediate- and

2.68-5.14; P < .0001 for the intermediate- vs. low-risk group; HR 8.52;

high-risk category was 76% (69–83), 46% (32–60), and 27% (2.3–52),

95% CI: 5.69-12.7; P < .0001 for the high- vs. low-risk group). Patients

respectively (Figure 1D) (c-statistic: 0.67).

belonging to the low-risk group had an OS superimposable to that of

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Spanish general population (Figure 1C). Similar findings were observed

encompassing the ATM gene in 30%-40% of cases and is associated

in the Brno series (HR 2.23; 95% CI: 1.45-3.44; P 5 .0002 for the inter-

with a short time to treatment, short progression-free-survival, and

mediate- vs. low-risk group; HR 3.93; 95% CI: 2.48-6.2; P < .0001 for

inferior OS after single agent fludarabine treatment.36,37 Del(17p) and

the high- vs. low-risk group) (Supporting Information Figure 3). The

del(11q) are considered to define high-risk CLL based on FISH-cytoge-

biomarkers-only CLL prognostic model segregated patients with differ-

netics.38 Although IGHV mutational status and adverse FISH cytoge-

ent TTFT among 337 subjects with stage A CLL from an independent,

netics are included in virtually all prognostic systems6,24,39–44 a model

prospectively collected external series (Figure 1D) (c-statistic: 0.67).

based only on these two biomarkers has not been proposed. Our

Finally, the prognostic model applied to all patients with CLL independ-

hypothesis was that a biomarkers-only prognostic model based on

ently of their age (Figure 1E,F) (c-statistic: 0.68).

IGHV mutational status and FISH cytogenetics would be as useful as others models based on a larger number of variables and could be used

4 | DISCUSSION

either alone or along with clinical stages.

In the last few decades the management of patients with CLL has sub-

in three distinct prognostic groups on the sole basis of IGHV mutational

stantially improved and, as a result, the median OS of subjects with this

status and FISH cytogenetics. Importantly, the low-risk group (IGHV

4

form of leukemia has increased from 5-6 years to more than 10 years.

mutated and no poor risk FISH-cytogenetics) identified around 50% of

However, the individual prognosis continues being extremely variable

patients with CLL whose OS in the investigated series did not differ

and therefore prognostication is an important component in the man-

from that of sex- and age-matched general population and a projected

agement of patients with CLL. Developed more than 30 years ago, clin-

10-year OS over 80%. At the other end of the spectrum, the high-risk

ical staging systems based on physical examination and blood cell

group (IGHV unmutated and adverse FISH cytogenetics) captured

counts have been the mainstay for estimating prognosis in patients

around 30% of patients with a projected OS at 10 years from diagnosis

Indeed, this study shows that patients with CLL can be separated

2,3

Afterwards, a plethora of markers have shown to add dis-

of less than 30%. In between, patients with intermediate-risk disease

criminant power to Rai and Binet clinical stages, among them IGHV

(either IGHV unmutated or adverse FISH-cytogenetics) had a projected

mutational status,14,15 cytogenetic abnormalities as detected by

10-year OS of 52% and 34% in the Barcelona and Brno series, respec-

FISH,16,17 lymphocyte doubling time,18,19 cell markers (e. g., ZAP70,

tively. The differences observed between the two series are explained

with CLL.

CD38, CD49d), 25

20–23

24

serum markers (B2M, thymidine-kinase), 26

27

micro-

by the poorer characteristics of the Brno series. The validation of the

In addition, prognosti-

prognostic model in patients with poorer features than the discovery

cation in CLL is gradually shifting from clinical parameters to

series demonstrates its clinical applicability across different forms of

biomarkers and from prognostic to predictive factors.28,29 Moreover,

the disease. We have also demonstrated that this prognostic model

massive genomic analyses have led to the identification of gene muta-

separates groups of patients with different outcome within clinical

tions (e. g., NOTCH1, SF3B1, BIRC3) which correlate with clinical

stages, particularly those with early disease. This is important as most

RNAs,

BCR-stereotypes,

and epigenetics.

30–32

outcomes

; however, these abnormalities are not yet used in clini-

patients with CLL are currently diagnosed in early clinical stage.

cal practice. Recently, a CLL-IPI that includes five parameters (age,

The biomarkers-only (IGHV mutational status and FISH cytogenet-

IGHV mutational status, del17p, beta2-microglobulin and Rai or Binet

ics) has notable strengths. First, it has been obtained and validated in

clinical stages) has been proposed and validated.7–10

three large independent series representative of the general population

To be extensively applicable and clinically actionable prognostic

of patients with CLL, thus avoiding biases related to patients’ selection;

models should be simple and based on standardized, robust and vali-

second, it is simple, easy to apply and to remember; third, it separates

dated parameters.28,29 One of the most important, and still unparalleled

three groups of patients with a sizeable proportion of patients; fourth,

advances in CLL, is that in this disease IGHV genes can be either

it applies to both younger and older persons with CLL; and fifth, it can

mutated (͠ 60% of cases) or unmutated (͠ 40% of cases), a fact that

be combined with clinical stages. Importantly, patients with low-risk

modulates several important pathogenetic pathways and separates two

disease as defined in this study had an excellent outcome independ-

different forms of disease. While most patients with mutated IGHV

ently of the Rai or Binet clinical stage, underlining that biological fea-

genes have indolent disease, favorable biomarkers and good prognosis,

tures are those actually shaping the outcome of patients with CLL.

those with unmutated IGHV genes tend to have rapidly progressive

There is a small proportion of patients with CLL in whom TP53 aberra-

clinical course, unfavorable biomarkers and short survival.14,15 There-

tions can be observed in the absence of del(17p).30,37 In the Barcelo-

fore, the IGHV mutational status is not only a key CLL biologic feature

na’s series 3% of patients presented TP53 mutation with no del17p;

but also a prognostic backbone around which revolve many other out-

not surprisingly, these cases did not modify the results of the study

come indicators, either favorable (“mutated” CLL) or unfavorable

(data not shown). Patients receiving targeted therapies (i.e., BCR signal

(“unmutated” CLL). In turn, del(17p)/TP53 mutations can be found in

inhibitors, BCL2 antiapoptotic agents), were not well represented in

5%-50% of patients depending on the study time point, prior therapy

our cohorts and should be investigated. However, there is data show-

and disease characteristics, and predict poor response to chemo

ing that IGHV mutational status and del17p are associated with a

(immuno)therapy.16,17,33,34 The prognostic importance of IGHV muta-

poorer outcome of patients treated with BCR signal inhibitors.45,46

tional status and del(17p) has been highlighted in a recent meta-analy35

sis.

Besides,

del(11q)

includes

a

minimally

deleted

region

The prognostic model has implications in the management of patients with CLL. While most patients with high-risk disease require

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early intervention, around 50% of patients with low-risk disease do not need therapy at diagnosis. Moreover, these patients may have a survival equivalent to that of sex- and age-matched controls, independently of the clinical stage. In line with this, recent reports have shown that, among other parameters (e. g., achievement of CR with no detectable residual disease), patients treated with fludarabine, cyclophosphamide and rituximab (FCR) displaying mutated IGHV and no del17p may achieve durable (> 10 years) complete responses.47–49 Interestingly, in our series only 30%-35% of patients were initially treated with FCR or other forms of chemoimmunotherapy. The best treatment strategy for patients with low-risk disease should be defined in clinical trials. cIn conclusion, the biomarkers-only prognostic model based on the two most robust CLL biomarkers (i.e., IGHV mutational status and FISH-cytogenetics) presented in this article is a simple and pragmatic approach to the prognostication of patients with CLL and could be useful in daily practice and in clinical trials.

ACKNOWLE DGMENTS n This work was supported by the Red Tematica de Investigacio Cooperativa en Cancer RT 06/0020/002051 and RD12/0036/0023 and by Instituto de Salud Carlos III (ISCIII) FISS PI080304 and ICGCCLL Genome Project, Generalitat de Catalunya 2009SGR1008. TB was supported by an “Emili Letang” grant. The Czech team was supported by Ministry of Health of the Czech Republic grants AZV 1531834A/2015 and AZV 15-30015A/2015 and by Ministry of Education, Youth and Sports of the Czech Republic project NPUII - CEITEC 2020 (LQ1601). This work was presented in part at the Annual Meeting of the American Society of Hematology. San Diego, CA, 2016.

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The authors declare no conflict of interest.

~olas N, Rozman C. Lymphocyte [18] Montserrat E, Sanchez-Bisono J, Vin doubling time in chronic lymphocytic leukaemia: Analysis of its prognostic significance. Br J Haematol. 1986;62:567–575.

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S UPPORTING INF ORMATION Additional Supporting Information may be found online in the supporting information tab for this article.

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simplifies the CLL-IPI. Am J Hematol. 2017;92:375–380.

prising only two biomarkers (IGHV mutational status and FISH cytogenetics) separates patients with different outcome and https://doi.org/10.1002/ajh.24660