The complex karyotype in hematological malignancies: a comprehensive overview by the Francophone Group of Hematological Cytogenetics (GFCH) - Nature
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Leukemia www.nature.com/leu
REVIEW ARTICLE
The complex karyotype in hematological malignancies: a
comprehensive overview by the Francophone Group of
Hematological Cytogenetics (GFCH)
✉
F. Nguyen-Khac 1,2,3 , A. Bidet4, A. Daudignon5, M. Lafage-Pochitaloff6,7, G. Ameye 8, C. Bilhou-Nabéra9,23, E. Chapiro1,2,3,
M. A. Collonge-Rame , W. Cuccuini11, N. Douet-Guilbert12,13, V. Eclache14, I. Luquet15, L. Michaux8, N. Nadal16, D. Penther17,
10
B. Quilichini18, C. Terre19, C. Lefebvre20, M.-B. Troadec 12,13 and L. Véronèse21,22
© The Author(s), under exclusive licence to Springer Nature Limited 2022
Karyotype complexity has major prognostic value in many malignancies. There is no consensus on the definition of a complex
karyotype, and the prognostic impact of karyotype complexity differs from one disease to another. Due to the importance of the
complex karyotype in the prognosis and treatment of several hematological diseases, the Francophone Group of Hematological
Cytogenetics (Groupe Francophone de Cytogénétique Hématologique, GFCH) has developed an up-to-date, practical document for
helping cytogeneticists to assess complex karyotypes in these hematological disorders. The evaluation of karyotype complexity is
1234567890();,:
challenging, and it would be useful to have a consensus method for counting the number of chromosomal abnormalities (CAs).
Although it is not possible to establish a single prognostic threshold for the number of CAs in all malignancies, a specific consensus
prognostic cut-off must be defined for each individual disease. In order to standardize current cytogenetic practices and apply a
single denomination, we suggest defining a low complex karyotype as having 3 CAs, an intermediate complex karyotype as having
4 CAs, and a highly complex karyotype as having 5 or more CAs.
Leukemia (2022) 36:1451–1466; https://doi.org/10.1038/s41375-022-01561-w
INTRODUCTION counted and that when multiple clones are present, each
The complexity of a karyotype is related to its negative prognostic independent aberration is counted only once. However, ISCN
impact. Therefore, the prognostic risk of complexity has to be 2020 does not specifically define a CK because these definitions
determined for each malignancy. The first studies of the complex (used for cytogenomic assessment of the prognostic risk) are
karyotype (CK) were performed in the 1980s, using chromosome disease-specific. Hence, the Francophone Group of Hematological
banding analysis (CBA). In 1981, Berger et al. defined karyotype Cytogenetics (Groupe Francophone de Cytogénétique Hématologi-
complexity in acute nonlymphocytic leukemia as the presence of que, GFCH) decided to comprehensively review CK definitions and
three or more different CAs in the malignant clone and/or their prognostic value in the various hematological neoplasms for
variation (i.e., changes from cell to cell, despite the presence of which the CK is relevant. When applicable, we also discuss
common abnormalities testifying to a clonal origin) [1]. In 1985, genomic complexity (GC), which can be analyzed using other
Juliusson et al. showed that three or more CAs were associated cytogenomic techniques (e.g. chromosomal microarrays (CMAs),
with poor overall survival (OS) in mature B cell disorders [2]. Yunis next-generation sequencing (NGS), whole-genome sequencing
et al. reported that in myelodysplastic syndromes, the presence of (WGS) and optical genome mapping).
three or more CAs was associated with poor survival [3]. The The present review has been prepared by a panel of 20 expert
International System for Human Cytogenomic Nomenclature specialists in hematological malignancies, each with an interna-
(ISCN) 2020 recently included a comprehensive guide to counting tional track record in their own field. Each section was written by a
CAs [4]. ISCN 2020 specifies that only clonal abnormalities must be panel subgroup and then reviewed by the full panel.
1
Cell Death and Drug Resistance in Lymphoproliferative Disorders Team, Centre de Recherche des Cordeliers, INSERM UMRS 1138, Paris, France. 2Sorbonne Université, Paris,
France. 3Service d’Hématologie Biologique, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France. 4CHU Bordeaux, Laboratoire d’Hématologie Biologique, F-33000 Bordeaux, France.
5
Institut de Génétique Médicale - Hôpital Jeanne de Flandre - CHRU de Lille, Lille, France. 6Laboratoire de Cytogénétique Hématologique, Hôpital Timone Enfant, AP-HM,
Marseille, France. 7Aix Marseille University, CNRS, INSERM, CIML, Marseille, France. 8Center for Human Genetics, Katholieke Universiteit (KU) Leuven, Leuven, Belgium. 9Service
d’Hématologie Biologique, Hôpital Saint-Antoine, Paris, France. 10Service de Génétique Biologique-Histologie, CHU Besançon, Besançon, France. 11Laboratoire d’Hématologie,
Hôpital Saint-Louis, AP-HP, Paris, France. 12Univ Brest, Inserm, EFS, UMR 1078, GGB, Brest, France. 13CHRU Brest, Service de génétique, Unité de génétique chromosomique, Brest,
France. 14Laboratoire d’Hématologie, Hôpital Avicenne, AP-HP, Bobigny, France. 15Laboratoire d’Hématologie, Institut Universitaire du Cancer de Toulouse Oncopole, CHU
Toulouse, Toulouse, France. 16Service de génétique chromosomique et moléculaire, CHU Dijon, Dijon, France. 17Laboratoire de Génétique Oncologique, Centre Henri Becquerel,
Rouen, France. 18Département Hématologie Cellulaire/Cytogénétique, Biomnis, Lyon, France. 19Laboratoire de Cytogénétique, Centre Hospitalier de Versailles, Versailles, France.
20
Laboratoire de Génétique des Hémopathies - CHU Grenoble Alpes, Grenoble, France. 21EA 7453 CHELTER, Université Clermont Auvergne, Clermont-Ferrand, France. 22Service
de Cytogénétique Médicale, CHU Estaing, Clermont-Ferrand, France. 23Deceased: C. Bilhou-Nabéra. ✉email: florence.nguyen-khac@aphp.fr
Received: 24 November 2021 Revised: 24 March 2022 Accepted: 28 March 2022
Published online: 16 April 2022F. Nguyen-Khac et al.
1452
HEMATOLOGICAL MALIGNANCIES prompt the practitioner to screen for TP53 mutations and
deletions, since a biallelic state further worsens the poor
prognosis associated with a CK. For CKs, the absence of HCK
MYELODYSPLASTIC SYNDROMES (MDS) and TP53 mutations is associated with an intermediate-like IPSS-R
A CBA is required for the proper classification of MDS with the risk [6]. A recent, very large study of both clinical and cytogenomic
World Health Organization (WHO)’s current system. A CK is a features found that patients with TP53 mutations and a CK have
strong predictor of a poor prognosis, as defined in the current the poorest outcomes [14].
Revised International Prognostic Scoring System (IPSS-R) [5].
Translocations. Translocations are rare in MDS (≈2.5%) and
Definition, counting, frequency, and prognostic value of correspond to more aggressive outcome only when associated
the CK with a CK [15, 16].
Definition. According to the IPSS-R, a CK corresponds to the
presence of 3 or more CAs [5]. More precisely, a CK with 3 CAs is Complexity as assessed with other genomic techniques
associated with a poor prognosis, and a CK with 4 or more CAs is Fluorescence in situ hybridization (FISH). FISH can be of value for
associated with a very poor prognosis (Table 1) [5]. Moreover, detecting a TP53 deletion in a CK that (when combined with a
Haase et al. designated a CK with 5 or more CAs as a highly TP53 mutation) characterizes a TP53 multi-hit state and thus
complex karyotype (HCK) [6]. defines a very high risk (HR) MDS [13].
Counting. International guidelines count one abnormality each CMAs. About 70–80% of de novo MDS patients harbor gains and
for monosomies, trisomies, structural abnormalities, and translo- losses that can be detected by single-nucleotide polymorphism
cations [7]. In the IPSS-R [8], CAs are counted only in the clone (SNP) arrays [17]. Arenillas et al. applied SNP arrays when CBA had
presenting the highest number of CAs–even for unrelated clones. been unsuccessful and found that 11% of these cases had a CK
Some years after developing the IPSS-R, the same authors [18]. The CMA analysis of normal-karyotype MDS revealed very
demonstrated that calculating the number of CAs in the entire few cases (2%) with copy number alterations (CNAs) >10 Mb, and
sample yielded a greater prognostic accuracy [9], and recom- only 0.2% of the cases corresponded to a CK [19]. CMAs can
mended classifying karyotypes with independent clones harbor- characterize CAs more precisely in the context of MDS CK [20].
ing more than two CAs per sample (and not per clone) as CKs [9]. Chromothripsis (CTH) can also be identified by using a CGH array
This was in agreement with Chun et al. [7]. (aCGH); it is found in about 1% of cases of MDS and is associated
with a CK [21].
Frequency. In de novo MDS, 5–9% of the karyotypes are complex
with 3–7% presenting 4 or more CAs [5, 8, 10]. About 37% of NGS and gene mutations. Mutations in MDS-associated genes
patients with therapy-related MDS (t-MDS, i.e. secondary MDS) other than TP53 are underrepresented in cases of CK-MDS, relative
harbor a CK, and most of these (31%) have 4 or more CAs [10]. to non CK-MDS [6]. For example, the frequency of mutations in
splicing genes is 10% for CK-MDS and 45% for non CK-MDS [6].
Prognostic value. For MDS and t-MDS, the karyotype is con-
sidered to be the most prominent independent prognostic factor Composite prognostic scoring systems that include the CK
for OS and the time to progression to acute myeloid leukemia and/or CAs
(AML) in the current IPSS-R [5, 8, 10]. CKs with 3 CAs and CK with 4 The IPSS-R for MDS combines the five cytogenetic risk groups with
or more CAs are the most accurate cytogenetic predictors of a refined categories for bone marrow blasts and cytopenia [5]. Some
poor prognosis and a very poor prognosis, respectively. experts are now advocating the inclusion of genetic features in
prognostic scoring systems for MDS [6, 13]. Bersanelli et al.
Special aspects of the CK in MDS suggested a prediction model based on clinical, cytogenetic and
The monosomal karyotype (MK). The MK was initially described in genomic/genetic features [14]. They identified eight groups –
AML. It corresponds to two or more autosomal monosomies or a notably those including gene mutations in the machineries for
single autosomal monosomy combined with at least one mRNA splicing and DNA methylation. The group with a SF3B1
structural CA (excluding markers or rings) [11]. About 75–80% of mutation was associated with the best outcome, whereas the
MDS patients with a CK have a MK—due mainly to −5 and/or −7. group with a TP53 mutation and/or a CK was associated with the
The prognostic impact of the MK (independently of the CK) on the worst outcome.
OS of MDS patients is still subject to debate [9, 10].
Treatment of CK-MDS
Deletion of 5q [del(5q)]. While del(5q) as the sole abnormality Of the most recently developed therapeutic agents, the BCL2
or combined with one additional chromosomal abnormality inhibitor venetoclax might delay disease progression in cases of
(ACA) (excluding −7/7q aberrations) is associated with a good HR-MDS [22]. Some chemotherapeutic agents like CPX-351 or APR-
prognosis, CKs (including del(5q)) are correlated with a poor 246 (the latter restores wild-type TP53 functions in TP53-mutant
prognosis [8]. CKs are more frequent in cases of MDS with an cells) might be of value in HR-MDS. It was recently demonstrated
unbalanced 5q translocation than in MDS with interstitial del that the combination of APR-246 and azacitidine was safe and
(5q) (95.2% vs. 32.2%) and are associated with clonal evolution, efficacious in a cohort of MDS patients with a TP53 mutation and
more TP53 mutations, and significantly shorter OS, the CK (in most cases) a CK [23, 24].
being the only independent adverse prognostic factor in this
study [12]. Conclusion
CK has strong prognostic value in MDS; according to Chun et al.
TP53 alteration. About 55% of MDS with a CK harbor TP53 accurate, standardized counting of CAs is therefore warranted [7].
mutations, and most of them (86%) present an HCK (5 or more It is noteworthy that TP53 mutations have significant prognostic
CAs) [6]. The CK is specifically associated with TP53 multi-hit value in patients with CK-MDS; given the availability of a
state (mutation, deletion, copy-neutral loss of heterozygosity promising drug (APR-246), the evaluation of TP53 alterations
(cnLOH) affecting the TP53 locus—most of which are biallelic), might directly benefit MDS patients—especially in those
relative to the TP53 monoallelic group [13]. The CK should with a CK.
Leukemia (2022) 36:1451 – 1466F. Nguyen-Khac et al.
1453
Table 1. CKs with a prognostic impact*.
Hematological Definition of a CK Frequency Prognostic impact Prognostic scoring References
malignancies system (PSS)
MDS de novo MDS and de novo MDS OS, time to IPSS Greenberg 1997
t-MDS CK with CAs = 3 progression to AML CAs > = 3: Poor [163]
CK with CAs = 3 2% IPSS-R$ Mauritzon 2002
CK with CAs > 3 CK with CAs > 3 CAs = 3: Poor [164]
3–7% CAs > 3: Very Poor Kantarjian, 2008
t-MDS [165]
CK with CAs = 3 Schanz 2012 [8]
6% Greenberg 2012
CK with CAs > 3 [5]
31% Kuendgen 2021
[10]
Adult AML After exclusion of All AML OS, EFS ELN Byrd 2002 [28]
WHO-designated 10–12% CAs > = 3: Adverse Schoch 2004 [32]
recurring CAs§ AML > 60y Schoch 2005 [36]
ELN 23% Grimwade 2010
3 or more CAs secondary [27]
MRC AML/t-AML Döhner 2017 [26]
4 or more CAs up to 25% Bager 2018 [47]
Daneshbod 2019
[31]
MPN and MDS/MPN 3 or more CAs CML CML PMF Bacher 2009 [62]
1% Blast crisis IPSS, DIPSS, Hussein 2010 [66]
PMF PMF, PV, ET, CMML MIPSS70 + v2 Gangat 2011 [64]
7.5% OS, time to CAs > = 3: Such 2011 [73]
PV, ET progression to AML Unfavorable Wang 2014 [72]
3–8% CMML Guglielmelli 2018
CMML CPSS, CPSS-Mol [65]
5–8% CAs > = 3: High risk Hochhaus 2020a
classification [57]
Adult T-ALL 5 or more CAs 7–13% EFS Moorman 2007
Excluding cases with a [80]
recurrent translocation Marks 2009 [83]
Lafage-Pochitaloff
2014 [84]
CLL 3 CAs = low-CK CK: 11–19% TTFT, PFS, OS Puiggros 2017
4 CAs = intermediate- HCK: 4–8% [104]
CK Rigolin 2017 [105]
5 or more CAs = high- Baliakas 2019
CK [101]
Excluding +12, +19,
+other CAs
MCL 4 or more CAs, 19–59% TTFT, OS Sarkozy 2014
including the t(11;14) [124]
Greenwell 2018
[125]
Obr 2018 [126]
a atypical; AML acute myeloid leukemia; CA chromosomal abnormality; CK complex karyotype; CLL chronic lymphocytic leukemia; CML chronic myeloid
leukemia; CMML chronic myelomonocytic leukemia; EFS event-free survival; ELN European Leukemia Net; HCK highly complex karyotype; MCL mantle cell
lymphoma; MDS myelodysplastic syndrome; MPN myeloproliferative neoplasm; MRC Medical Research Council; OS overall survival; PFS progression free-
survival; T-ALL T-cell acute lymphoblastic leukemia; t therapy related; TTFT time-to-first treatment; U unclassified; WHO World Health Organization.
*only hematological malignancies for which CK has a prognostic impact are reported here.
$ In therapy-related MDS, only the IPSS-R is applicable.
§ t(8;21), inv(16) and t(16;16), t(9;11), t(v;11)(v;q23.3), t(6;9), inv(3) and t(3;3), t(9;22).
ACUTE MYELOID LEUKEMIA (AML) Definition, counting, frequency, and prognostic value of the CK
Introduction Definition. Whilst the CK has been consistently linked to a poor
CAs are observed in around 50% of AML patients, with the CK outcome in adult AML, there is still no consensus on the definition
being one of the most frequent aberrations. According to the of complexity: some experts define the CK as the “presence of a
most recent adult European LeukemiaNet (ELN) recommenda- clone with more than 3 CAs” [27] whereas others apply a criterion
tions, CK are defined by 3 or more unrelated CAs in the absence of of “3 or more CAs” [28, 29]. Currently, all the prognostic
WHO-designated recurring translocations or inversions–t(8;21), inv classifications (other than the UK Medical Research Council
(16) or t(16;16), t(9;11), t(v;11)(v;q23.3), t(6;9), inv(3) or t(3;3), t(9;22) (MRC) system) define the CK as “3 or more CAs” (Table 1).
[25, 26]. As CK does not appear to have the same impact in adult
AML as in rarer pediatric AML, we have drafted a separate Counting. Only the adult MRC system specifies counting rules: a
paragraph on the latter disease. balanced translocation is defined as one abnormality, whereas
Leukemia (2022) 36:1451 – 1466F. Nguyen-Khac et al.
1454
two CAs should be counted for a derivative chromosome resulting no structural aberrations or monosomies) had an adverse
in the gain and loss of chromosomal material [27]. In most studies, outcome, regardless of the number of chromosomal gains.
however, a derivative chromosome is considered as a single CA However, the results of two studies have challenged the
[7, 30]. assignment of the HK to the HR group. Luquet et al. [43] defined
HK as karyotypes with more than 48 chromosomes without a
Frequency. A CK (3 or more CAs) is observed in ~10–12% of cases structural rearrangement, and none of their patients had more
[28, 29]. The incidence of a CK is higher in older patients (up to than 59 chromosomes. The HK appears to represent a subgroup of
23% over the age of 60) [31] with secondary AML (25%) or t‐AML uncommon AMLs (less than 1%) and might be better classified in
(26.9%) [32]. New CAs appear in 30 to 40% of relapsed patients. the intermediate prognostic group. Chilton et al. [44] defined the
The frequency of new CK is higher in patients who relapse after an HK with 49–65 chromosomes and stated that those with
allograft than in conventionally treated patients (50.0% vs. 12.2%, chromosome number variations only should be classified into
respectively) [33]. the intermediate risk group.
Prognostic value. The ELN has defined three major cytogenetic Pediatric AML. The CK’s prognostic value is subject to debate. A
risk categories: favorable, intermediate, and unfavorable. The CK is CK (3 or more CAs) is observed in 8–18% of cases of pediatric
included in the unfavorable group [26]. AML with a CK aged under AML (mainly in children under the age of 3 y) and correspond to
60 and 60 or over have complete remission (CR) rates of 48 and a high prevalence (~25%) of French-American-British (FAB) M7
39% and a 3-year (y) survival of 9 and 3%, respectively [34]. In the morphologies [30, 45–47]. In the Berlin-Frankfurt-Munster (BFM)
revised MRC cytogenetic classification [27] based on 5,876 98 trial, a CK defined as “three or more alterations, including one
patients under 60 y, more than 3 unrelated CAs provided the structural and no favorable aberration or MLL (KMT2A) rearran-
most informative cut-off, predicting a significantly poorer OS. gement” was found in 8% of de novo AML cases and was
Conversely, for Byrd et al. [28], the low CR rate and 5 y OS, and the associated with a poor 5 y event-free survival (EFS) rate [45]. In
high cumulative incidence of relapse justified a unique CK the larger MRC10–12 study (which did not exclude 11q23/KMT2A
category defined by 3 or more CAs. Other experts considered cases), the CK frequency was higher (18%) but did not have
that in addition to the number of CAs, the type of CA might significant prognostic value [30]. In the most recent BFM-2004
influence the prognosis. The Southwest Oncology Group showed protocol [46], CKs were observed in 59 of the 642 cases (9%) but
that patients with a CK and involvement of chromosomes 5 or 7 only MK+ patients (3% of cases) had a poor prognosis. Indeed,
had significantly lower CR and OS rates [35]. Schoch et al. [36] MK+ status was a strong, independent predictor of a poor
suggested that a typical CK should meet all the following criteria: outcome [46]. Lastly, the recent NOPHO-DBH study found that
(a) the absence of any of the known recurring balanced the CK (prevalence: 15%) was an independent predictor of poor
abnormalities leading to fusion genes, (b) 3 or more CAs, (c) loss EFS and OS and that the MK (prevalence: 5%) was associated
of at least one of the 5q, 7q or 17p chromosomal regions, and (d) with refractory disease and poor EFS [47].
loss of at least one additional area in the regions 18q21q22, 12p13
or 16q22q24 or the gain of 11q23q25, 1p33p36, 8q22q24 or Complexity as assessed with other genomic techniques
21q11q22. The median OS was significantly shorter in the patients CMAs. Several groups have used SNP arrays to examine bone
with a typical CK. More recently, Mrózek et al. [37] defined a marrow samples from AML patients. For Renneville et al. [48]
“typical CK” with 5q, 7q, and/or 17p abnormalities and an about 30% of the patients with a normal karyotype had a least one
“atypical” CK lacking these abnormalities. A typical CK was SNP array lesion, and those harboring abnormal SNP lesions had
associated with older age, fewer bone marrow blasts, more TP53 significantly worse clinical outcomes - whatever the number of
mutations, and a shorter OS. abnormalities. Renneville et al. did not give a definition of
karyotype complexity with this technique. In a recent study of a
Specific aspects of the CK in AML large number adult patients with AML, CTH (as identified using
Favorable abnormalities and the CK. Acute promyelocytic leuke- SNP array data) was observed in 7% of cases. CTH was found to be
mia with t(15;17)(q24;q22)/PML::RARA and “core binding factor strongly associated with older age, CK, TP53 alterations (mutation
AML” (CBF AML, which includes AML with inv(16)(p13.1q22) or t and/or deletion), and del[5q]. Furthermore, CTH per se is
(16;16)(p13.1;q22)/CBFB::MYH11 and AML with t(8;21)(q22;q22.1)/ associated with a very poor prognosis [49].
RUNX1::RUNX1T1) are assigned to the favorable risk group [26, 31].
In these types of AML, the presence of ACAs does not worsen the NGS. A recent study [50] found a 94% concordance rate for
prognosis [25–27] – although some studies have come to the shallow WGS vs. CBA in the detection of all ELN CNAs. Total
opposite conclusion [38, 39]. genomic loss (defined as a total loss of at least 200 Mb per WGS
dataset) was found to be a better marker of a poor prognosis than
The monosomal karyotype. In 2008, Breems et al. defined the MK the CBA definition of a CK; this was in line with Breems et al.’s
for the first time in non CBF-AML [11]. The MK accounts for 13% of original finding, whereby the MK had more prognostic value that
all AML patients and 22% of AML patients aged 60 or over [11, 40]. the CK [11].
It is independently associated with an unfavorable outcome and is
included in the ELN’s guidelines [26]. Composite prognostic scoring systems that include the CK
The MK has a worse prognosis than CK in AML [11]; the 4-year and/or CAs
OS rates in the unfavorable MK and non-MK groups are 4% and The ELN has established a composite prognostic scoring system
26%, respectively [11]. This difference in OS between “CK+MK+” that combines cytogenetic and molecular abnormalities. As
and “CK+MK−” patients might depend on the definition of CK. OS mentioned above, the CK is included in the HR group [26].
is significantly longer for “CK+MK−” patients when the CK is A multistage, random-effects model has recently been devel-
defined as 3 or more CAs but not when it is defined as 4 or more oped. It generates individual predictions on the likelihoods of
CAs [41]. remission, relapse and mortality and can facilitate personally
tailored therapeutic decisions [51].
The hyperdiploid karyotype (HK). At present, the HK is considered
to be a CK and is classified in the ELN’s HR category [26]. Indeed, Treatments and the CK
Stolzel et al. [42] defined the HK with a broad range of 49–80 Several new drugs have promising levels of efficacy, especially for
chromosomes and found that patients with a “pure” HK (i.e. with AML patients in the HR subgroups (including patients with a CK).
Leukemia (2022) 36:1451 – 1466F. Nguyen-Khac et al.
1455
CPX-351. CPX 351 is approved for patients with AML and (1–15%) are predictive of death by blast crisis emphasizes the
myelodysplasia-related changes or with t-AML. In a French real- critical role of CBA in identifying end-phase CML [54].
life study of these two groups of patients receiving induction with
CPX-351, 34% had a CK and 27% had an MK. In contrast to the MK, Chromosomal abnormalities in Ph-negative cells. Some CAs in Ph-
and TP53 or PTPN11 mutations, the CK was not found to be negative cells (especially −7) reportedly have a negative impact
associated with a poor prognosis [52]. on OS. In these cases, CKs are rare (7%) and data on outcomes are
insufficient. In this context, the emergence of a CK might be a sign
Combination therapy: venetoclax (a BCL2 inhibitor) and azacitidine of progression to MDS or AML [59].
(a hypomethylating agent). A phase III trial in treatment-naive AML
patients who were not eligible for intensive chemotherapy evaluated Complexity as assessed with other genomic techniques
azacitidine–venetoclax vs. azacitidine–placebo. The CK frequency Additional genomic aberrations detected by SNP arrays are not
was similar in the two groups (~25%). OS and the incidence of predictive of the disease outcome after imatinib therapy.
composite CR were greater in patients who received azacitidine- However, the outcome analysis did not consider the notion of
venetoclax than in those treated with azacitidine-placebo - even in complexity [60].
the adverse cytogenetic risk subgroup. However, the impact of the
CK per se was not studied [53]. Composite prognostic scoring systems that include the CK
and/or CAs
Conclusion The ELN experts currently recommend considering patients with HR-
At present, the CK is defined as “3 or more CAs” by all the ACAs (including the CK) at diagnosis as HR, according to the new
prognostic classifications (other than the UK MRC) and still has European Treatment and Outcome Study long-term survival score [57].
major prognostic value in AML. Given that novel therapies appear
to be efficacious in patients with a CK, CBA upon diagnosis is still Treatments and the CK
essential for guiding the choice of treatment. The presence of a CK at diagnosis predicts a poorer response to
treatment with TKIs [57]. Over the course of CML, resistance may
be caused by BCR::ABL1 kinase domain mutations and by clonal
MYELOPROLIFERATIVE NEOPLASMS (MPNS) AND CHRONIC cytogenetic changes (the appearance of ACAs). However, not all
MYELOMONOCYTIC LEUKEMIA (CMML) ACAs are equivalent markers of progression: the CK is associated
Introduction with worst survival and is placed in the unfavorable group.
MPNs are chronic malignancies that can transform into secondary
myelofibrosis or progress to AML. They include chronic myeloid Conclusion
leukemia (CML), primary myelofibrosis (PMF), polycythemia vera The CK is a reliable prognostic marker for the chronic phase and
(PV), essential thrombocythemia (ET). The MDS/MPNs are myeloid blast crisis and during follow-up in CML - especially in cases of
neoplasms that are associated with either some features of MDS disease progression or treatment failure.
or others more consistent with MPN. They include chronic
myelomonocytic leukemia (CMML).
POLYCYTHEMIA VERA, ESSENTIAL THROMBOCYTHEMIA, AND
Counting PRIMARY MYELOFIBROSIS
The usual method for counting CAs (as described above) is The prevalence of CAs in Ph-negative MPNs is 15–35% for PV,
applied [7]. 3–7% for ET and 40–45% for PMF [61].
Definition, frequency, and prognostic value of the CK
CHRONIC MYELOID LEUKEMIA (CML) Definition. For all Ph-negative MPNs, the definition of a CK as 3 or
Definition, frequency, and prognostic value of the CK more CAs is consensual (Table 1).
Definition. A CK is defined as 3 or more CAs, including the
Philadelphia (Ph) chromosome resulting from t(9;22)(q34;q11) Frequency. When considering abnormal karyotypes, the CK is
(Table 1) [54]. infrequent (~7.5% in a cohort of patients with PV, ET, PMF or an
unclassifiable MPN) [62].
Frequency. A CK is rare at diagnosis (prevalence: ~1%) and
usually emerges during the course of CML; it is observed in 22% of Prognostic value. Survival in PV is adversely affected by an
patients in the blastic phase [55]. abnormal karyotype, which is a risk factor for leukemic
transformation [63]. In ET, an abnormal karyotype is not predictive
Prognostic value. Approximately 10–12% of CML patients exhibit of OS or leukemic transformation. CKs are not specifically
ACAs at diagnosis [56]. These anomalies are separated in HR group mentioned in the literature data on PV and ET. Conversely, in
(including the CK, +8, +Ph, i(17q), +19, -7/7q-, 11q23 and 3q26 PMF, CK is associated with a poor subsequent OS [64–67].
aberrations) and low-risk group (all others) considering the ACAs
impact on the response to tyrosine kinase inhibitors (TKIs) and the Special features related to the CK in Ph-negative MPN
risk of progression [54, 57]. It is noteworthy that the CK is According to the ELN experts, CBA is not mandatory at diagnosis;
predictive of a poor prognosis (poor OS) in the blastic phase [55]. karyotype may be performed to screen for clonal features,
Lastly, a recent report suggested that ACAs in childhood CML are depending on each individual laboratory’s preferences. Hence,
not significantly related to the prognosis [58]. the prevalence of a CK at diagnosis might have been under-
estimated [68].
Specific aspects of the CK in CML
Cytogenetic monitoring during treatment. Cytogenetic monitoring Complexity as assessed with other genomic techniques
is no longer mandatory during follow-up but is indicated in cases of CMAs do not detect more complex cytogenetic profiles than
disease progression or an unsatisfactory treatment response. The karyotype and may not help to refine the prognosis. Apart from
emergence of HR-ACAs (including the CK) is a marker of treatment cytogenetic features, a recently developed molecular HR signature
failure or resistance and must prompt a change in the treatment for PV and ET has introduced the concept of molecular complexity
strategy [57]. Moreover, the fact that HR-ACAs with low blast count [69]. Short-term transformations are characterized by a complex
Leukemia (2022) 36:1451 – 1466F. Nguyen-Khac et al.
1456
molecular landscape (with a median of 7 somatic mutations), group (like the CPSS), red blood cell transfusion dependency,
whereas long-term transformations have a less complex profile [70]. peripheral leukocytosis, and bone marrow blasts [77].
Composite prognostic scoring systems that include the CK Treatments and the CK
and/or CAs CK is not a significantly predictor of the response to hypomethy-
In PMF, several prognostic scores include cytogenetic data (Table 1). lating agents [78]. However, the prognostic factors associated with
The IPSS for PMF and the DIPSS-Plus consider the CK to be an the allograft outcome include the cytogenetic profile. In particular,
unfavorable risk factor associated with a poor outcome [64, 66]. The patients assigned into the HR group (on the basis of the karyotype
genetically inspired prognostic scoring system (GIPSS) is based and the prognostic scoring system) reportedly have worst
exclusively on mutations and CAs: the CK is placed in the unfavorable outcomes after transplantation [79].
or very HR karyotype groups, which are independent factors for poor
survival [67]. Lastly, the mutation- and karyotype-enhanced interna- Conclusion
tional prognostic scoring system 70 (MIPSS70) was developed as a The presence of CK at diagnosis or during disease progression is
guide to transplantation strategy for patients under 70 years but did predictive of poor survival of CMML. As such, the CK is included in
not encompass cytogenetic criteria [65]. In version 2.0 of the prognostic stratification systems.
MIPSS70+ (which was improved by adding CBA information), the CK
is placed in the unfavorable karyotype category [65].
ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)
Treatments and the CK Introduction
The karyotype and mutations should always be considered when The CK’s prognostic value in ALL has been studied mainly in Ph-
making decisions about transplantation [71]. Patients with an positive ALL and in adult Ph-negative (B- and T-cell) ALL. To the
adverse karyotype should undergo an allograft or at least be best of our knowledge, the CK in Ph-negative childhood ALL has
closely monitored for disease progression, so as not to miss a never been studied in this respect.
favorable window for transplantation.
Definition, frequency, and prognostic value of the CK
Conclusion Definition. In adult Ph-negative ALL, CK has been defined as
The presence of a CK at diagnosis is predictive of poor survival in cases lacking an established translocation and presenting with at
PMF. Likewise, presence of a CK during the course of disease is least 5 unrelated CAs within the 40–50 chromosome modal
predictive of poor survival in progressing or treatment-refractory number range [80]. In Ph-positive adult ALL, CK has been defined
cases of Ph-negative MPN. as at least 3 [81] or 5 unrelated CAs [82].
Frequency. A CK (defined as 5 or more CAs) is found in 5–8% of
CHRONIC MYELOMONOCYTIC LEUKEMIA adult Ph-negative ALL cases, 5–6% of B-cell cases, and 7–13% of
CAs have been reported in 20–40% of CMML patients and are T-cell cases [80, 83–85]. Three and 5 CAs were found respectively
especially frequent in advanced phases of the disease. in 49% and 25% of cases of adult Ph-positive ALL [81, 82, 86].
Definition, frequency, and prognostic value of the CK Prognostic value. In cases of adult Ph-negative ALL, a CK (5 or
Definition. A CK is defined as 3 or more CAs (Table 1). more CAs) was associated with shorter EFS [80]. This association
with a poor prognosis was confirmed for cases of T-cell ALL in the
Frequency. The CK is infrequent in CMML, and concerns about same cohort [83]. Conversely, in a larger trial with more intensive
4–8% of patients [72–74]. therapy, the CK’s prognostic value was only confirmed for T-cell
ALL (Table 1) [84, 85].
Prognostic value. There is a strong association between specific Although the prognosis of Ph-positive ALL is markedly
CAs, the risk of AML, and OS. The Spanish cytogenetic risk improved by the adjunction of a TKI, the prognostic value of
stratification system defines three groups according to the OS: CK ACAs and the CK has not been systematically assessed in
is included within the poor-risk category [73]. This stratification therapeutic trials. In trials of TKIs in adults with ALL, ACAs
was used to develop a new CMML-specific prognostic scoring variously have no prognostic value [87] or are predictive of a poor
system (CPSS) [75]. By analogy with the IPSS-R for MDS patients, prognosis (possibly related to −7 [88]), as previously reported
CMML patients with 4 or more CAs were shown to have a before the TKI era in adults [81] and children [89]. In other adult
significantly shorter OS than patients with 3 CAs [72]. trials, the CK (whether defined as 3 or more CAs [86] or 5 or more
CAs) [82] has no prognostic value.
Specific aspects of the CK in CMML
MKs were reassigned as HR by a Mayo Clinic-French consortium. Isolated Specific aspects of the CK in ALL
MKs were infrequent (3%) and generally overlapped with CKs [74]. The karyotype profile of CKs in ALL. In adult Ph-negative ALL, the
CK is mainly due to combinations of secondary CAs; these are
Complexity as assessed with other genomic techniques classical ALL deletions and monosomies (like del(6q), del(7p)/−7,
CMAs detect CAs in 75% of patients with MDS/MPN [76]. Overall, del(9p)/−9, del(12p), del(13q)/−13, del(17p)/−17) and classical
patients with an abnormal karyotype have a more complex B-ALL gains (like +X and +21) [77, 81, 83].
cytogenetic profile with array approaches than with CBA only. ACAs are observed in 60–70% of cases of adult and pediatric
However, none of the CMA analyses have shown that GC has a Ph-positive ALL: +Ph, del(7p)/−7, del(9p)/−9, +1q, +8, +21, +X.
prognostic impact in CMML. Moreover, in 8% and 23% of childhood and adult cases
respectively, a HK (51–67 chromosomes) is observed with
Composite prognostic scoring systems that include the CK chromosomal gains similar to those in Ph-negative HK ALL (with
and/or CAs the exception of +2 and +Ph) [81, 89].
The CPSS combines cytogenetic data, the WHO subtype, the FAB
classification, and red blood cell transfusion dependency [75]. The hyperdiploid karyotype. As mentioned above, the HK is
More recently, the CPSS-mol score has been developed: it includes excluded from the CK in Ph-negative ALL cases [80], whereas HK is
RUNX1, NRAS, SETBP1, and ASXL1 mutations, the cytogenetic risk present in about one third of CKs in Ph-positive ALL [80, 89].
Leukemia (2022) 36:1451 – 1466F. Nguyen-Khac et al.
1457
The monosomal karyotype. The definition of an MK in ALL is intermediate-CK (defined as 4 CAs), and high-CK (HCK, defined as
based on the original AML study [11]. In adult Ph-negative ALL 5 or more CAs) demonstrated that only the latter was an
(and after the exclusion of the low hypodiploid poor outcome independent prognostic factor for OS [101]. In a literature review,
subtype, characterized by multiple autosome losses), the MK did Jondreville et al. suggested defining CK as 3 or 4 CAs and HCK as 5
not have significant prognostic value in B-cell or T-cell ALL [84, 85]. or more CAs, with the exception of cases with +12, +19, +other
Conversely, in the TKI era, the MK (mainly due to −7 or −9) is aberration(s) associated with a good prognosis (Table 1) [98].
associated with a poor prognosis in adults with Ph-positive ALL [82].
Counting. The method used to count CAs is not always clearly
Complexity as assessed with other genomic techniques explained in the literature. The main interstudy difference relates
CMAs. In the cohort of adult patients with T-ALL in whom the CK to counting the CAs in all the clones or only in the clone with the
was predictive of a poor prognosis, aCGH analysis of 53 cases highest number of abnormalities [101, 102]. Jondreville et al. have
identified an average of 6 CNAs per case. Most of these CNAs were published simple guidelines for counting aberrations in CLL, based
cryptic in karyotypic terms. The most frequent deletions on their experience and their review of the literature: count 1
concerned the tumor suppressor genes CDKN2A/2B (9p21), RB1 aberration for each item between commas in all clones and
(13q14), and TP53 (17p13). However, a putative correlation with subclones; count a single change only once if present in several
the CK was not studied. Interestingly, patients with TP53 deletions subclones; count each numerical change (including –Y, −X, +15),
had a significantly worse outcome [90]. balanced translocation, simple structural change, complex struc-
CMAs can identify complex chromosomal rearrangements, such tural change and marker as 1 aberration; count 1 aberration for
as the intrachromosomal amplification of chromosome 21 tetraploidy (92 chromosomes) or near-tetraploidy (81–103 chro-
(iAMP21) in pediatric B-ALL The iAMP21 results from breakage- mosomes); do not count constitutional aberration; count 1
fusion-bridge cycles, followed by CTH; this results in an abnormal aberration for a FISH abnormality only if it is observed in the
chromosome 21, with 3 or more extra copies of the RUNX1 gene karyotype [98].
[91]. The iAMP21 is a rare provisional WHO entity associated with a
poor prognosis [25], although patients treated as having high-risk Frequency. Overall, a CK is present in 11% to 19% of treatment-
B-ALL have an improved outcome [92]. In the largest yet study of naive CLL patients, and in up to 40% of patients with relapsed/
iAMP21, a CK (3 or more CAs) and an HCK (5 or more CAs) were refractory (R/R) CLL [98, 103]. An HCK is observed in 4 to 8% of
observed in 52% and 23% of cases, respectively [92]. treatment-naive patients [100, 101, 103].
NGS. Whereas TP53 mutations have been linked to the CK in AML Prognostic value. In some studies, the negative impact of a CK on
and MDS, this has not been the case in ALL; however, TP53 OS was independent of other parameters [104, 105]. Not all CKs
mutations are strongly associated with the low hypodiploidy/near are necessarily equivalent. Rigolin et al. have suggested two types
triploidy poor prognosis entity in B-ALL [93]. Furthermore, in about of CK: CK1 includes balanced translocations, deletions, monosomy,
half of the pediatric cases, TP53 mutations are found in non- or trisomy; and CK2 includes unbalanced translocations, chromo-
malignant cells as a constitutional abnormality characteristic of some additions, insertions, duplications, and ring, dicentric and
the neoplasia predisposition Li Fraumeni Syndrome; this has marker chromosomes. Relative to CK1, CK2 is associated with
important consequences for genetic counseling and the choice of shorter OS and a shorter TTFT [106]. Baliakas et al. have suggested
a family allograft donor [93]. a hierarchical model (based on cytogenetics, TP53 status, and IGHV
status) in which the HCK exhibited the worst prognosis; this
Conclusion contrasted with CK cases (3 or 4 CAs) in whom aggressive disease
The value of the CK in B cell and Ph-positive ALL is still subject to occurred only in the presence of TP53 abnormalities, whereas
debate, although a CK with 5 or more CAs is considered to be a patients with a CK and +12, +19 displayed an indolent profile
marker of a poor prognosis in adult T-cell ALL - emphasizing the [101]. Lastly, a recent publication by Visentin et al. has
need to fully characterize the patient’s cytogenomic status demonstrated that the presence of CK2 or an HCK at diagnosis
(notably by performing CBA) upon diagnosis of ALL [94]. are predictive of Richter syndrome [102].
Specific aspects of the CK in CLL
CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) CKs including +12,+19. CKs with +12, +19 appear to be
Introduction associated with a good prognosis and have to be classified
In view of the low natural in vitro mitotic activity of CLL cells, the separately [98, 101, 107, 108].
use of a 72-hour culture with CpG oligonucleotides and interleukin
2 has increased the CA detection rate and thus renewed interest in CKs and del(13q), TP53 disruption, and IGHV status. The CK might
performing CBA in this disease [95]. CAs are detected in up to 80% reverse the good prognosis associated with isolated del(13q)
of CLL patients, with a median of one abnormality per treatment- (detected by FISH in the Dohner et al.’s hierarchical model) and
naïve patient [96, 97]. The most frequent abnormalities are del mutated IGHV status. It also worsen the poor prognosis associated
(11q), del(13q), del(17p) and +12. At present, TP53 alterations (del with TP53 aberrations (for a review, see [98]).
(17p) and/or TP53 mutations) and unmutated IGHV status have
been linked to a poor prognosis for patients undergoing Complexity as assessed with other genomic techniques
chemoimmunotherapy. The CK has recently emerged as a novel CMAs. CMAs can detect a median of 1 CNA in about 90% of
prognostic marker in CLL. treatment-naïve patients with CLL [109]. A number of CMA-based
studies of CLL have reported an association between GC (i.e. an
Definition, counting, frequency, and prognostic value of the increasing number of CNAs) and adverse outcomes. The definition
CK of GC varies from one study to another: from 2 or more CNAs to 5
Definition. There is still no consensus on the definition of a CK in or more CNAs or a total CNA length >5 Mb. Most of these were
CLL [98]. Conventionally, a CK is defined as 3 or more CAs, retrospective studies of patients with CLL having undergone
including numerical and structural CAs [95, 96, 99]. Using this chemo(immuno)therapy. Despite these limitations, it was demon-
definition, CK was found to be associated with shorter time-to-first strated that GC is correlated with a shorter TTFT and shorter OS
treatment (TTFT) and shorter OS [95, 100]. A more recent study [109–112]. Interestingly, a recent study of risk stratification by CBA
of the CK, separated into low-CK (defined as 3 or 4 CAs), vs. CMA analysis in CLL showed that both methods were
Leukemia (2022) 36:1451 – 1466F. Nguyen-Khac et al.
1458
concordant for prediction of TTFT and OS [113]. Another study Counting
found that only a high level of GC (defined as 5 or more CNAs) was The usual method for counting CAs (as described above) is
an independent predictor of a short TTFT and short OS [112]. applied to non-Hodgkin lymphomas [7].
Interestingly, the phase III MURANO study of venetoclax-rituximab
vs. bendamustine-rituximab in relapsed CLL showed that high GC
(as assessed with a CMA) had a major impact on progression free- MANTLE CELL LYMPHOMA
survival (PFS) in both treatment arms, even though venetoclax- MCL is characterized genetically by the t(11;14)(q13;q32) translo-
rituximab was more efficacious than bendamustine-rituximab cation. Overall, about 80% of patients with MCL carry non-random
[114]. CTH cannot be detected by CBA; it corresponds to a ACAs [124]. In the updated WHO classification, MCL was
complex rearrangement but is counted as a single event in the subdivided into indolent mantle cell lymphoma (iMCL, defined
published studies. CTH is predominantly found in CLL cases with by a leukemic presentation in the presence or absence of
CK, TP53 disruption, and/or del(11q), and is associated per se with splenomegaly) and conventional mantle cell lymphoma (cMCL,
a poor outcome in CLL [112, 113]. defined by a nodal presentation and requiring the rapid initiation
of chemotherapy). Three morphological variants (classical, blastoid
NGS and gene mutations. Since 2011, a large number of recurring and pleomorphic) have been described.
gene mutations (including TP53 and ATM mutations) have been
reported in CLL. With the exception of TP53, none of these Definition, frequency, prognostic value of the CK
mutations has clear prognostic value (for a review, see [115]). Definition. In two large series of patients with MCL, a CK was
When both TP53 deletions and mutations are analyzed, TP53 defined as 4 or more CAs, including the t(11;14) translocation [125].
disruption is significantly associated with a CK [101]. The
combination of mutations in TP53, ATM, and SF3B1 genes might Frequency. In two studies of MCL, a CK was detected in about
be associated with a poor prognosis in R/R CLL [116]. It has been 19% and 59% of the patients [124, 125]. This disparity might be
reported that the cumulative number of driver gene mutations due - at least in part - to the different proportions of cases of iMCL
and/or CNAs is correlated with worse outcomes (TTFT and OS) in each cohort.
[117, 118].
Prognostic value of the CK. Three retrospective studies have
Composite prognostic scoring systems that include the CK shown that a CK is significantly associated with poorer OS and
and/or CAs treatment-free survival (TFS), independently of the other baseline
Several prognostic scoring systems have been suggested for CLL. prognostic factors (the MCL international prognostic index, the
Most of them are based on or include cytogenetic data. Döhner’s Ki67 proliferation index, and the morphological variant) [124–126].
hierarchical prognostic model (established in 2000) was based on
five risk categories using 4 FISH probes [119]. Rossi et al. Specific aspects of the CK in MCL
suggested an integrated mutational-cytogenetic model, based iMCL vs. cMCL. The clinical distinction between cMCL and iMCL is
on TP53, BIRC3, NOTCH1, and SF3B1 abnormalities, del(11q), +12, mirrored by differences in GC. Indeed, the incidence of a CK was
and del(13q) [120]. More recently, Baliakas et al. included the CK significantly higher in cMCL than in iMCL [124]. Within the iMCL
and +12, +19, TP53 and IGHV status [101] in their prognostic subgroup, patients with a CK seemed to have a shorter TFS time
scoring system. The latter scoring system is the only one that than patients with a simple karyotype [124].
includes the CK.
Morphological variants. The blastoid variant of MCL features a
Treatments and the CK significantly greater number of CAs than the classical variant does
Several studies have reported the negative impact of a CK on PFS [124, 127, 128]. Moreover, a tetraploid karyotype or subclones
and/or OS after conventional treatments for CLL, including chemo appear to be much more common in the blastoid variant (59%)
(immuno)therapies. Data for targeted therapies (such as Bruton (B) than in the classical variant (9%) [128–130].
TKIs and the BCL2 inhibitor venetoclax) are also available. Most of
the studies were performed in R/R patients and assessed the impact TP53/17p deletion and the CK. Two studies showed that the CK
of a CK with 3 or more CAs. In patients treated with a BTKI, CK might was significantly associated with TP53/17p deletion but did not
be associated with a greater risk of progression or transformation report on the outcomes [124, 126].
(for a review, see [98]). In a recent study, increased karyotype
complexity was shown to be an independent predictor of shorter Complexity as assessed with other genomic techniques
PFS and OS [121]. In patients receiving venetoclax, CK appeared to CMAs. CMAs have not been compared with karyotyping for the
have an influence on PFS and OS in two recent retrospective studies assessment of GC in MCL. Among patients with iMCL, GC (defined
[122, 123]. Thus, it appears that patients with a CK do not respond to as having more than 5 CNAs in an SNP array analysis) was
targeted therapies as well as other patients. associated with shorter TFS [131]. Furthermore, the incidence of a
high degree of GC was greater in cMCL than in iMCL [131]. Overall,
Conclusion a high number of CNAs was associated with shorter OS, regardless
The CK appears to have prognostic value in CLL - even in of the MCL subgroup [131].
patients receiving targeted therapies. Since these molecules can
now be used as first-line treatments, the prognostic impact of Chromothripsis. CTH has been found 28% of cases of MCL and is
CKs and HCKs now warrants careful analysis - especially in more frequent in cMCL than iMCL [132]. The presence of CTH was
prospective studies. We need to understand how a patient also closely associated with a very high degree of GC [132]. A high
becomes resistant to a particular therapy and whether or not the incidence of CTH (92%) has been described for blastoid and
CK is involved. pleomorphic variants, whereas no cases with CTH were detected
in patients with the classical variant [133] - reflecting the very high
level of chromosomal instability in aggressive variants.
LYMPHOMA
Introduction Conclusion
In lymphoma, the CK has prognostic value in mantle cell Hence, the CK has become an important biomarker for the
lymphoma (MCL) only (Table 1). prognosis and clinical management in MCL–emphasizing the
Leukemia (2022) 36:1451 – 1466F. Nguyen-Khac et al.
1459
relevance of ACAs in this disease. The predictive value of the CK or Definition, counting, frequency, and prognostic value of the CK
a complex genome on the rapid initiation of treatment in iMCL Definition, counting, and frequency. Using CBA, only 30–35% of
subgroup needs further confirmation. patients present abnormal karyotypes, which are often associated
with advanced disease. Earlier studies demonstrated that about
half of cases of MM are characterized by hyperdiploidy (mainly
SPECIAL ASPECTS OF THE CK IN OTHER B-CELL LYMPHOMAS trisomies of odd chromosomes in hyperdiploid multiple myeloma,
Follicular lymphoma (FL) HK-MM), while most of the remaining cases have a pseudodiploid
The t(14;18)(q32;q21) translocation is present in about 85% of or hypodiploid karyotype with translocations mostly involving the
cases of FL. Most of the karyotypes contain a broad spectrum of immunoglobulin heavy chain (IGH) locus on chromosome 14q32
ACAs, leading to GC even at the time of diagnosis [134, 135]. There (IGH translocated MM) [145]. All cases of HK-MM have a CK, with
is no clear definition of a CK in FL; Johnson et al. considered a CK an average of 5 trisomies per patient, and about 90% of cases of
to have 3 or more ACAs, excluding the t(14;18), while Mitsui et al. IGH translocated MM carry 3 or more structural anomalies with an
included the t(14;18) [134, 135]. When these different rules are average of 6.7 breakpoints per patient [146].
applied, a CK is detected in 62 to 69% of cases [134, 135]. A CK
does not appears to have a clear prognostic impact on the Prognostic value. As expected, most of the successfully karyo-
response to rituximab or the risk of early relapse or transformation - typed patients present a relatively high level of abnormal bone
the latter two features being important predictors of the course of marrow plasma cells (PCs), this is why karyotype complexity
the disease. Thus, the CK’s prognostic impact in FL has not been cannot be associated with any prognostic impact in this biased
definitively assessed in a prospective trial and remains subject to context, even though HK-MM confers a good prognosis [146]. At
debate. present, counting CAs using CBA is not relevant for MM, mainly
because cases of MM with low-PC cannot be investigated using
Splenic marginal zone lymphoma (SMZL) this method. Therefore, FISH on isolated CD138-expressing PCs is
Two cytogenetic studies of large series of patients with SMZL now the mandatory cytogenetic analysis for MM [142, 143].
defined a CK as the presence of 3 or more CAs [136, 137]. The CK
was thus observed in 53 to 61% of cases [136, 137]. In a univariate Special features related to complexity in MM: FISH on isolated
analysis of the data in the European study, the presence of 2 or CD138-expressing PCs
more CAs was associated with a worse outcome and a greater risk Definition. Most routine FISH studies investigated a small number
of progression (relative to a simple karyotype) [136]. The Chinese of markers only (del[17p]/TP53, t(4;14) and sometimes t(14;16))
study found significant worse OS for patients with a CK - even in a which prevented complexity from being characterized [147].
multivariate analysis [137]. It, therefore, appears to be reasonable
to define a CK in SMZL as 3 or more CAs; however, the CK’s Counting. Many comprehensive studies have identified second-
prognostic significance remains unclear. ary CAs arising during the course of the disease, including gain
(1q), del(1p), del(17p)/TP53, del(13q), and secondary translocations
Waldenström macroglobulinemia (WM) involving 8q24/MYC. Both primary and secondary CAs can
In WM, a CK has been defined as at least 3 CAs and was detected influence the course of the disease and the treatment response,
in 14% of cases [138]. In this work, CK had no impact on the and some have independent prognostic value [148]. Moreover,
outcome, response rate or risk of progression [138]. In a very the simultaneous occurrence of deleterious markers can modify
recent study, a CK (3 or more CAs) and an HCK (5 or more CAs) the prognostic stratification [149–152]. Most abnormalities have a
were nevertheless observed in 15% and 5% of cases, respectively significant negative or positive impact on OS, some has protective
[139]. An HCK was associated with shorter PFS and OS [139]. CBA, effect, others worsen clinical outcome [148, 153]. Their frequency
therefore, remains a valuable analysis for the diagnosis of WM and depends on the number of markers tested, which is limited by the
might also provide relevant prognostic information. nature of the sample and the techniques used.
B-cell prolymphocytic leukemia (B-PLL) Prognostic value and scores. The Mayo clinic investigators first
A very recent collaborative study involving our group determined that the presence of two HR factors from among t
described the cytogenetic and molecular characteristics of (4;14), t(14;16), t(14;20), del[17p] and gain[1q] (double-hit mye-
the largest yet series of B-PLL [140]. A CK and an HCK were loma) or 3 or more HR factors (triple-hit myeloma) has a negative
identified in 73% and 45% of cases, respectively. Neither the impact on OS [144, 154]. In a series of 159 patients tested for eight
CK or the HCK was significant correlated with the outcome, markers using FISH, 20% had HR markers, and 4.5% and 1% were
although the patients with the worst outcome had a 17p/TP53 double- and triple-hit, respectively. The mean ± standard
deletion and a MYC abnormality (gain or translocation) - deviation OS time was 6 ± 4.2 months in patients with two HR
emphasizing the critical role of this specific combination in this abnormalities, 32.0 ± 25.6 in those with single HR abnormality, and
aggressive disease [140]. 57.0 ± 9.6 months in those lacking an HR abnormality.
Lastly, it should be noted that cytogenetic complexity per se Another study of 1273 newly diagnosed patients with MM
does not have significant diagnostic or prognostic value in identified a HR “double-hit” subgroup with either biallelic
patients with diffuse large B-cell lymphomas, other aggressive inactivation of TP53 or amplification (≥4 copies) of CKS1B (1q21),
B-cell lymphomas, and T-cell lymphomas. accounting for 6.1% of the patients [155].
More recently, the Intergroupe Francophone du Myélome’s study
of most of CAs (including trisomies) led to the development of a
MULTIPLE MYELOMA (MM) prognostic score that takes account of the various CAs’ negative or
Introduction protective impacts [151] (Table 2).
The high degree of heterogeneity in MM outcomes is mainly
driven by CAs. The landscape of CAs in MM is now well Complexity as assessed with other genomic techniques
documented [141]. The International Myeloma Working Group High-sensitivity genome-wide analyses can detect more abnorm-
recommended incorporating CAs in the Revised International alities than FISH panel studies. However, these studies do not take
Staging System (R-ISS) for MM [142, 143]. Low, intermediate, and account of the notion of GC.
HR changes have been well defined, although some remain CMAs detects abnormalities in 85–100% of patients. The results
subject to debate [144, 145]. are often complex, with 1 to 74 (median: 10–20) abnormalities.
Leukemia (2022) 36:1451 – 1466You can also read
