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Chronic lymphocytic leukemia (CLL) is the most common leukemic disease in elderly patients. In Germany, the annual incidence in men is 7.4/100.000 and in women 4.8/100.000, and the median age of onset is between 70 and 75 years. The clinical and biological picture of CLL is very heterogeneous. The disease develops from mature B-cells, and is mainly due to the inhibition of apoptosis and dysregulation of proliferation in these cells. In many cases, CLL is preceded by an asymptomatic and unnoticed preliminary stage with proliferation of clonal B cells, which is known as monoclonal B-cell lymphocytosis (MBL).
According to the WHO classification 2017, chronic lymphocytic leukemia (CLL), as an indolent lymphocytic lymphoma characterized by a leukemic course, is one of the mature B-cell neoplasms. Differentiation from mantle cell lymphoma, follicular lymphoma or other lymphoma entities must be made by immunophenotyping, cytomorphology, FISH and histology.
Cytomorphologically, B-CLL frequently shows the phenomenon of "Gumprecht's nuclear shadow" in addition to the proliferation of mature lymphatic cells: These correspond to CLL cells which artificially burst on the slide when being spread. They occur, but do not prove the diagnosis. The typical B-CLL is distinguished from B-prolymphocytic leukemia (B-PLL), in which ≥ 55% of the lymphocytes show an immature appearance with a larger nucleus and a clearly visible nucleolus. In the rare transformation of a B-CLL into a Richter syndrome, blast like cells are found.
Characteristic for CLL is an expression of the B-cell markers CD19, CD20 and cyCD79a with simultaneous aberrant expression of the CD5 antigen. There is a weak surface expression of CD22. Specific for CLL is the weak expression of CD20 and the weak to missing expression of FMC7 and CD79b. Characteristically, weak expression of surface immunoglobulins with clonal light chain restriction is also observed. In general, CD23 is expressed, which is rarely the case in mantle cell lymphoma. In addition, compared to CLL, mantle cell lymphoma shows a stronger expression of surface immunoglobulins as well as a higher expression of CD22 and FMC7 and a higher expression of CD79b. Accordingly, the diagnosis of CLL from a single marker alone is not possible. Rather, the synopsis of all antigens examined and the use of the Matutes score derived from this has proven to be useful (Matutes et al. 1994, Moreau et al. 1997).
Immunophenotypic characteristics of B-CLL
- sCD22(+) or CD79b(+)
Monoclonal B-cell lymphocytosis of the CLL type (MBL) is distinguished from CLL: Here a monoclonal B-cell population < 5 x 109/L is found in peripheral blood; the immunophenotype corresponds to that of CLL. The patients are mostly asymptomatic and do not show any laboratory changes typical of neoplasm. Transformations into B-CLL are observed annually in 1-2% of all cases.
In CLL/PL (CLL with 10% to 54% prolymphocytes in peripheral blood) the immunophenotype often shows a stronger expression of CD20 and surface immunoglobulins (s-Ig) than in typical CLL. Furthermore, there is a weaker expression of CD23 and a positivity for CD22 and CD79b.
In prolymphocytic leukemia (B-PLL) (≥ 55% prolymphocytes in peripheral blood), there is no or only weak coexpression of CD5, surface expression of immunoglobulins and of CD20 is stronger; CD22 and FMC7 are also expressed.
In addition to establishing the diagnosis, immunophenotyping allows the detection of measurable residual disease (MRD) in CLL. The phenotype of CLL cells - CD19+CD20+CD79-CD5+ - clearly distinguishes them from normal B-lymphocytes. The MRD level in CLL is of prognostic relevance according to the results of several larger studies. A low MRD level during and after therapy is associated with longer progression-free survival (PFS) and prolonged overall survival (OS). Patients with negative MRD levels showed a longer PFS than patients with positive MRD levels, regardless of whether they are in complete or partial remission. Thus, MRD quantification allows an improved PFS prediction in patients who achieve both partial and complete remission (Kovacs et al. 2016, Böttcher et al. 2012).
Chromosomal analysis had previously played only a minor role in CLL, since the necessary cultivation of CLL cells in vitro was hardly successful. However, since the cultivation of CLL cells has been reliably possible, more abnormalities can be detected than with FISH analysis (Dicker et al. 2006).
Chromosome analysis can also be helpful in differentiating B-CLL from other mature B-cell neoplasm. It was shown that patients with inconspicuous findings in the FISH analysis but an aberrant karyotype in the chromosome analysis showed a shorter interval until the need for therapy and a shorter survival than patients who also showed a normal karyotype in the chromosome analysis (Rigolin et al. 2012).
The results of chromosomal banding analyses showed that the spectrum of cytogenetic alterations in CLL is wider than was apparent using the FISH methodology. Typical for CLL are genomically unbalanced events (Haferlach C et al. 2007). The most frequent alterations are 13q deletion, 11q deletion, trisomy 12, 6q deletion and 17p deletion. Rather rare changes are trisomy 3 or 3q gains, gains of 2p, 8q and 11q as well as translocations involving immunoglobulin loci (2p12 (Ig kappa), 14q32 (IgH), 22q11 (Ig lambda)) (Döhner et al. 1999, Stilgenbauer et al. 2002). The translocations t(11;14)(q13;q32), t(14;18)(q32;q21) and t(14;19)(q32;q13) are also rarely observed.
Approximately 20% of CLL patients show a complex aberrant karyotype in chromosome band analysis (≥ 3 aberrations) (Haferlach C et al. 2007; Haferlach C et al. 2010). Herling et al. 2016 showed that a complex aberrant karyotype is an independent prognostic factor that may even exceed the prognostic effect of TP53 alterations. Recent studies suggest that a complex aberrant karyotype is an independent unfavourable factor only from ≥ 5 aberrations on. However, a complex aberrant karyotype with 3 or 4 aberrations is only associated with an adverse prognosis if there is an additional TP53 deletion and/or a TP53 mutation. Complex aberrant karyotypes with a +12 and +19 have a favorable prognosis (Baliakas et al. 2019). Thus, a detailed analysis is necessary for the best possible prognostic classification.
Chromosome band analysis is not yet firmly established in the diagnosis of CLL, but could play an important role in the future due to new prognostic findings in complex aberrant karyotypes. Chromosome band analysis has already been included in the recommendations of the iwCLL (Hallek et al. 2018), the NCCN guidelines (status 2019) and the S3-CLL guideline. Beyond supporting the prognostic classification, chromosome band analysis can help to distinguish CLL from other indolent lymphomas.
With FISH analysis and a standard panel of FISH probes, genetic changes can be detected in approximately 80% of CLL patients. The most common chromosomal abnormalities are 13q deletion, followed by trisomy 12 and 11q deletion (Döhner et al. 2000, Hallek et al. 2008). The 6q deletion and the 17p deletion are observed less frequently. The FISH analysis is important for the prognostic assessment of both standard and more modern therapies. According to the Onkopedia guideline CLL, a FISH analysis should be performed to detect del(17p13) and further genetic testing for atypical phenotype to differentiate it from other indolent lymphomas. According to S3 guideline CLL, an additional examination for 11q deletion should be performed. Patients with del(11)(q22.3) may benefit from chemoimmunotherapy. The International CLL Workshop (iwCLL) recommends a del(11q) or del(17p) examination, a FISH examination for del(13q) and 12q gains in peripheral blood (Oncopedia Guideline CLL: Stand 04/2019, S3 Guideline 2018, Hallek et al. 2018).
Furthermore, the examination for a t(11;14)/IGH-CCND1 is useful to distinguish between CLL and mantle cell lymphoma. However, even a few distinct CLL - characterized with all classical criteria - may show a t(11;14).
In IGHV status, somatic mutations are determined in the variable region (V) of the heavy chain (H) of immunoglobulins (IG). About 60% of all CLL patients have a mutated IGHV status. The load of somatic hypermutations in a specific part of the B cell receptor - the so-called IGHV (immunoglobulin heavy chain variable) gene - is determined in comparison to the original DNA sequence. A presence of 2% or less mutations is called "unmutated" and a presence of more than 2% mutations is called "mutated". New classifications for the IGHV mutation status are Unmutated status ≤2% mutations, borderline status: 2.1-3% mutations and mutated status >3% mutations. A prognostic statement about the borderline IGHV mutation status is not yet possible (Davis et al. 2016). Since the result of the IGHV mutation analysis for a specific CLL population does not change over time, repeated analysis is usually not necessary. In about 30% of CLL, similar patterns were found in the B-cell receptor, a so-called stereotype (Messmer et al. 2004, Tobin et al. 2004). Stereotype means similarity of the amino acid sequence in the CDR3 region. Different stereotypic rearrangements have different prognostic meanings (Stamatopoulos et al. 2017). The different subgroups of stereotypic B cell receptors are called "subset". Subsets are more common in CLL with unmutated IGHV status (U-CLL) than in CLL with mutated IGHV status (M-CLL) (40% vs. 10%). Different "subsets" are associated with different prognoses of disease progression.
The IGHV mutation status has purely prognostic significance and can be determined at initial diagnosis according to S3 guidelines CLL, but should be performed at the latest at the time of therapy indication. The International CLL Workshop (iwCLL) also recommends a one-time assessment of the IGHV mutation status prior to therapy (Hallek et al. 2018). According to the Oncopedia Guideline CLL, therapy with ibrutinib should be performed if the IGHV status is not mutated.
Mutations in TP53, SF3B1, NOTCH1, ATM and BIRC3
For TP53 alterations a distinction must be made between mutations and deletions (17p-). TP53 mutations are changes in the base sequence within the gene and can only be detected by sequencing. A TP53 deletion results in the loss of genetic material of the short arm of chromosome 17 (17p), which spans the entire gene and can be detected by FISH, or by chromosomal analysis if the gene is large enough. At initial diagnosis the incidence of TP53 mutations is about 8%. TP53 deletions occur in about 4%, mostly in combination with a TP53 mutation but also alone (Zenz et al. 2010). In order to clarify the TP53 status of a patient comprehensively, a FISH analysis for 17p as well as a TP53 mutation analysis must therefore be performed. According to iwCLL guidelines (Hallek et al. 2018) TP53 aberrations should be investigated prior to therapy and the test should be repeated at each change of therapy. According to the S3 guidelines on CLL, the last determination of TP53 aberrations should be made no more than 12 weeks before therapy starts and otherwise it should be repeated, since TP53 aberrations can also occur only in the course of CLL (S3 guideline CLL 2018). In advanced stages and in refractory CLL the frequency of TP53 changes increases significantly (see Table 1).
SF3B1 mutations occur in about 6% of CLL patients. The incidence is significantly increased in refractory CLL patients (Table 1). SF3B1 mutations correlate with an unmutated IGHV status, ATM changes and a stereotypical IGHV3-21 rearrangement (subset #2). There is increasing evidence that these mutations are associated with an intermediate prognosis (Oscier et al. 2013, Stilgenbauer et al. 2014, Jeromin et al. 2014).
NOTCH1 mutations are common in CLL with an unmutated IGHV status and are associated with trisomy 12. NOTCH1 mutations are observed in about 10% of initial CLL diagnoses and are associated with an approximately 20-fold increased risk of transformation to DLBCL. There is evidence that patients with NOTCH1 mutations have an intermediate prognosis and experience no benefit from the addition of rituximab to fludarabin/cyclophosphamide chemotherapy (Stilgenbauer et al. 2014). However, this has yet to be confirmed in further independent studies.
ATM changes can be caused by both mutations and deletions (11q-). Mutations occur in approximately 6% of CLL patients at diagnosis. Deletions of 11q22 always contain the ATM gene. In about 30% of the cases with a 11q deletion there is also an ATM mutation. These patients show an intermediate prognosis, although there is evidence that if a deletion and a mutation occur simultaneously, a less favourable prognosis is to be expected than with only one ATM mutation (Austen et al. 2007, Skowronska et al. 2012). The limited response to chemotherapy in patients with ATM alteration seems to be improved by the addition of rituximab (Stilgenbauer et al. 2014). Since the gene is very large and therefore difficult to sequence, an analysis is only recommended for specific questions.
BIRC3 alterations can be divided into BIRC3 mutations and BIRC3 deletions. The incidence of BIRC3 alterations at initial diagnosis is 4%, but is higher in refractory patients. The gene BIRC3 is located on the long arm of chromosome 11 near the ATM gene. In 80% of CLL patients with ATM deletion, BIRC3 is also deleted. An adverse prognosis is assumed for patients with BIRC3 alterations (Rossi et al. 2013).
IGHV status is an important prognostic marker of CLL
IGHV status is a very important prognostic marker in CLL. The non-mutated status is already associated with a less favourable prognosis in early stage CLL (Damle et al. 1999, Hamblin et al. 1999).
The presence of a stereotypic B-cell receptor may affect prognosis. Recently, it has been shown that patients with a stereotypic IGHV3-21 rearrangement (subset #2) have a significantly reduced time to treatment regardless of the mutation status (Baliakas et al. 2015, Jeromin et al. 2016). However, there is evidence that the prognosis is modulated by additionally present molecular and cytogenetic changes (Jeromin et al. 2016).
In addition, it was shown that subset #1 and #8 are frequently associated with a very aggressive clinical course in U-CLL, whereas subset #4, which is mostly present in M-CLL, has an indolent course (Stamatopoulos et al. 2017).
The abnormalities detected by FISH have prognostic significance. Döhner et al. (2000) developed a hierarchical model, whereby when multiple aberrations occur, the prognosis is determined by the most unfavourable genetic modification (see Table 2). The presence of a 17p deletion or an 11q deletion indicates a less favourable disease course compared to the "normal karyotype" in FISH, whereas the presence of a 13q deletion alone is associated with a more favourable prognosis. Patients with trisomy 12 show a similar prognosis as those with normal karyotype.
Chromosome band analysis can provide additional prognostic information in addition to the FISH examination. Several studies have shown that a complex aberrant karyotype is an independent prognostic factor that may even exceed the prognostic effect of TP53 alterations (Herling et al. 2016). Recent results show that only a complex karyotype with ≥ 5 aberrations is an independent unfavourable factor. However, a complex aberrant karyotype with 3 or 4 aberrations is only associated with an adverse prognosis if there is an additional TP53 deletion and/or a TP53 mutation. Complex aberrant karyotypes with +12 and +19 show a favourable prognosis (Baliakas et al. 2019).
CLL: TP53 mutations have an adverse prognosis
An adverse effect on overall survival and time to treatment was shown for TP53 alterations. The incidence of TP53 mutations is 8-12% and of TP53 deletions 4-7%, but it is significantly higher in advanced stages and in refractory CLL. TP53 mutations are often associated with 17p/TP53 deletions, but correlate independently with an adverse prognosis (Döhner et al. 2000, Stilgenbauer et al. 2014, Zenz et al. 2010). If one TP53 allele is mutated and the other is deleted, so that no functional TP53 can be formed, this leads to an additive negative effect (Stengel et al. 2016). Biallelic mutations or monoallelic mutations with CN-LOH (copy-neutral loss of heterozygosity) with a dominant negative effect rarely occur (Goh et al. 2011).
The prognostic panel according to Rossi et al. 2013 considers both molecular genetic and cytogenetic markers. Patients are divided into four risk groups:
- High risk: TP53 or BIRC3 alterations
- Intermediary risk: NOTCH1 or SF3B1 mutations or 11q deletion
- Low risk: trisomy 12 or normal karyotype
- Very low risk: only 13q deletion
This model can be used both for initial diagnosis and during the course of the disease.
Subclones with mutations (especially in the gene TP53) also show the same unfavourable course as patients with corresponding changes in the main clone (Landau et al. 2013, Rossi et al. 2014). Next-generation sequencing enables the detection of these subclonal mutations up to a clinically relevant mutation load of approx. 3%.
In order to be able to better predict the individual course of events, a systematic prognosis index has been developed (International Prognostic Index CLL-IPI, Table 3 and Table 4).
Table 3: International Prognostic Index for CLL (Variable)
Deletion and/or mutation
Rai I-IV or Binet B-C
Table 4: International Prognostic Index for CLL (Risk groups)
5-year survival rate (%)
Hoechstetter et al. 2020 showed for stage A CLL according to Binet that in addition to age > 60, ß2-microglobulin >3.5 mg/L, an unmutated IGHV status, a del(17p) in FISH, also lymphocyte doubling time <12 months, del(11q), trisomy 12, male sex and NOTCH1 mutations are associated with a shorter survival and a shorter time to first treatment (Hoechstetter et al. 2020). It should be noted that the TP53 mutation status was not evaluated in this study. The final prognostic model includes six independent risk factors weighted relative to the respective hazard ratio. The score can be calculated according to Table 5. Based on the sum of risk points, patients could be stratified into four risk groups, which were of prognostic relevance for the assessment of both overall survival and time to first treatment (TTFT) (Hoechstetter et al. 2020).
Table 5: Prognostic model developed on the basis of patient data from the CLL1 cohort (CLL1-PM)
IGHV mutation status
Lymphocyte doubling time
Age at baseline
Risk classification by total score
Very low risk: 0-1.5
Low risk: 2-4
High risk: 4.5-6.5
Very high risk: 7-14
A new international prognostic score (IPS-E) was developed for patients with asymptomatic early stage CLL. It provides a prediction of the time to first treatment (TTFT). Three factors with equal weighting (with 1 point each) were determined, which can independently predict TTFT. The factors are: an unmutated IGHV status, lymphocytes > 15x109/L and palpable lymph nodes. This results in 3 risk groups: Low risk (0 points), medium risk (1 point) and high risk (2-3 points). The probability of needing treatment increases from low risk to high risk patients (Table 6 and Table 7). TP53 aberrations play an important role in therapy decisions, but have no prognostic significance in determining the time to treatment (Condoluci et al. 2020).
Table 6: International Prognostic Score (IPS-E)
Table 7: Risk groups
|Cumulative incidence of treatment (5-years,%)|
There are associations between molecular cytogenetic changes (in FISH) and other prognostic markers. For example, CD38-positivity associated with an adverse prognosis (Hamblin et al. 2000, Ibrahim et al. 2001, Jelinek et al. 2001) occurs more frequently together with a higher number of FISH abnormalities and with high risk factors (17p-, 11q-). Furthermore, associations between 11q-deletions and 17p-deletions and an unmuted IGHV status are found (Stilgenbauer et al. 2002; Kröber et al. 2002). Associations of SF3B1 mutations with 11q deletions and NOTCH1 mutations with trisomy 12 have recently been discussed.
In addition, the detection of CD38 expression and cytoplasmic expression of ZAP70 is associated with an adverse prognosis. However, these parameters are of less clinical and therapeutic relevance today.
Baliakas et al. 2019 examined early stage CLL for different prognostic markers depending on the IGHV status. Unfavorable factors in patients with mutated IGHV status are TP53 aberrations, trisomy 12 and the stereotype IGHV3-21 (subset #2). In patients with unmutated IGHV status del(11q), TP53 aberrations and/or SF3B1 mutations and men showed a shorter time to first treatment.
If a patient is suspected of having CLL, the various guidelines recommend the following tests:
Onkopedia Guideline CLL (Status: April 2019)
Table 8: Tests to establish the diagnosis CLL
Complete blood count (CBC)
Leukocytes with differential blood count (microscopic differentiation), thrombocytes, haemoglobin, reticulocytes (for signs of anaemia)
Expression of CD19 and CD23
Coexpression of CD5
Weak or missing expression of CD220, CD79b, FMC7
Monoclonality of Igκ and Igλ
Table 9: Additional tests before treatment
* Data on the adverse prognosis of patients with deletion 17p13 are based on molecular cytogenetic analyses using FISH. The collective of patients with inactivation of p53 by mutations overlaps very much with that of patients with del 17p13, but is not completely congruent
S3 Guideline CLL (March 2018)
Table 10: Overview of tests and indications for initial and follow-up diagnostics
Prior to Therapy
FISH del(17p13) and TP53-mutation status
FISH del(13)(q14), del(6)(q21~23), +12
Chromosome band analysis
MRD-evaluation (Cytometry or molecular genetics)
shall: strong recommendation; should: recommendation; can: recommendation open
iwCLL Guidelines (Hallek et al. 2018)
Table 11: Baseline evaluation of patients with CLL
Tests to establish the diagnosis
CBC and differential count
Assessment before treatment
FISH del(13q), del(11q), del(17p), add(12) in peripheral blood
IGHV mutational status
Conventional karyotyping in peripheral blood lymphocytes (with specific stimulation)*
* Can be useful before therapy if an established methodology is available.
NCCN Guidelines (2019)
Table 12: Overview of NCCN investigation recommendations
+12, del(11q), del(13)(q), del(17p)
TP53 mutation, IGHV mutation status
Cytogenetic changes do not only allow an assessment of the prognosis. Rather, increasing data indicate that it is also possible to assess the response to certain therapies on the basis of the cytogenetic changes. This is of great importance, as many new substances have currently found their way into CLL therapy, whose efficacy also varies depending on the presence of certain genetic abnormalities (Hallek 2013, Byrd et al. 2015, O'Brien et al. 2015, Roberts et al. 2016, Onkopedia Guideline CLL: Status 04/2019).
Del(17p13) and TP53 mutations influence choice of first-line therapy
Del(17p13) and TP53 alterations are currently the only prognosis markers that already have a direct influence on the first therapeutic decision. Thus, the presence of TP53 mutations and/or TP53 deletions is prognostically unfavourable and associated with a lower response rate to commonly used standard chemotherapy (Oscier et al. 2013, Stilgenbauer et al. 2014). Since TP53 alterations may be added in the course of the disease, a TP53 analysis should be performed prior to any therapy decision in case of disease progression. Thus, the current Onkopedia guidelines recommend the use of ibrutinib in first-line therapy in patients with CLL requiring therapy and a TP53 alteration, regardless of their general condition (Onkopedia guideline CLL: 04/2019).
Recent studies suggest that patients with a complex aberrant karyotype respond less well to ibrutinib-based treatments (O'Brien et al. 2018, Thompson et al. 2015). However, these patients may benefit from treatment with venetoclax-obinutuzumab (Al-Sawaf et al. 2020)
IGHV mutation status
The IGHV status is an important prognosis marker. It does not change during the course of the disease and should therefore be determined once before a decision on therapy is made. Patients with an unmutated IGHV status have a shorter overall survival and need therapy earlier (Hamblin et al. Blood 1999). The Onkopedia guidelines for CLL recommend therapy with ibrutinib.
There are also mutations in other genes whose effects on the course of the disease and relevance to therapy are currently being investigated. These include the following, each with a frequency of less than 10%: BCOR, EGR2, FBXW7, MYD88, NRAS, POT1, KRAS, SAMHD1, XPO1.
Development of resistance under ibrutinib therapy
Treatment with ibrutinib may lead to the development of resistance mutations. Known affected genes are the BTK and PLCG2 genes (Woyach et al. 2014). Since mutations in these genes can only be detected after therapy is administered, an examination is only indicated in the case of non-response and not before the start of therapy.
Al-Sawaf et al. High efficacy of Venetoclax plus Obinutuzumab in patienst with complex karyotype and chronic lymphocytic leukemia. Blood 2020;135(11):866-870.
Arbeitsgemeinschaft der wissenschaftlichen medizinischen Fachgesellschaften e.V. (AWMF). Leitlinienprogramm Onkologie (Deutsche Krebsgesllschaft, D.K., AWMF) S3-Leitlinie zur Diagnostik, Therapie und Nachsorge für Patienten mit einer chronischen lymphatischen Leukämie (CLL). AWMF-Registernummer: 018-032OL (Stand: März 2018). 2018
Austen et al. Mutation status of the residual ATM allele is an important determinant of the cellular response to chemotherapy and survival in patients with chronic lymphocytic leukemia containing an 11q deletion.J Clin Oncol 2007;25(34):5448-5457.
Baliakas P et al. Not all IGHV3-21 chronic lymphocytic leukemias are equal: prognostic considerations. Blood 2015; 125:856-859.
Baliakas P et al. Cytogenetic complexity in chronic lymphocytic leukemia: definitions, associations, and clinical impact. Blood 2019;133(11):1205-1216.
Baliakas P et al. Tailored approaches grounded on immunogenetic features for refined prognostication in chronic lymphocytic leukemia. Haematologica 2019;104(2):360-369.
Binet JL et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer 1981;48(1):198-206).
Böttcher S et al. Minimal residual disease quantification is an independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: A mutlivariate analysis from the randomized GCLLSG CLL8 trial. J Clin Oncol 2012;30(9):980-988.
Byrd JC et al. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood 2015;125(16):2497-2506.
Condoluci A et al. International prognostic score for asymptomatic early-stage chronic lymphocytic leukemia. Blood 2020;135(21):1859-1869.
Damle RN et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 1999;94:1840–1847.
Davis Z et al. The outcome of chronic lymphocytic leukaemia patients with 97% IGHV gene identity to germline ist distinct from cases with <97% identity and similar to those with 98% identity. Br J Haematol. 2016;173(1):127-136.
Dicker F et al. Immunostimulatory oligonucleotide-induced metaphase cytogenetics detect chromosomal aberrations in 80% of CLL patients: a study of 132 CLL cases with correlations to FISH, IgVHstatus, and CD38 expression. Blood 2006;108(9):3152-3160.
Döhner H et al. Chromosome aberrations in B-cell chronic lymphocytic leukemia: reassessment based on molecular cytogenetic analysis. J Mol Med (Berl) 1999;77(2):266-281.
Döhner H et al. Genomic aberrations and survival in chronic lymphocytic leukemia. NEJM 2000;343(26):1910-1916.Goh AM et al. The role of mutant p53 in human cancer. J Pathol 2011;223(2):116-126.
Guièze R and Wu CJ. Genomic and epigenomic heterogeneity in chronic lymphocytic leukemia. Blood 2015; 126(4):445-453.
Haferlach C et al. Comprehensive genetic characterization of CLL: a study on 506 cases analysed with chromosome banding analysis, interphase FISH, IgV(H) status and immunophenotyping. Leukemia 2007 ;21(12):2442-2451.
Haferlach C et al. Toward a comprehensive prognostic scoring system in chronic lymphocytic leukemia based on a combination of genetic parameters. Genes Chromosomes Cancer 2010;49(9):851-859.
Hallek M et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 2008 ;111(12):5446-5456.
Hallek M. Signaling the end of chronic lymphocytic leukemia: new frontline treatment strategies. Blood 2013;122(23):3723-3734.
Hallek M et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and suportive management of CLL. Blood 2018; 131:2745-2760.
Hamblin TJ et al Immunoglobulin V genes and CD38 expression in CLL. Blood 2000;95(7):2455-2457.
Hamblin TJ et al. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 1999;94(6):1848-1854.
Herling CD et al. Complex karyotypes and KRAS and POT1 mutations impact outcome in CLL after chlorambucil-based chemotherapy or chemoimmunotherapy. Blood 2016;128(3):395-40.
Hoechstetter MA et al. Prognostic model for newly diagnosed CLL patients in Binet stage A: results of the multicenter, prospective CLL1 trial oft he German CLL study group. Leukemia 2020;34:1038-2051.
Ibrahim S et al. CD38 expression as an important prognostic factor in B-cell chronic lymphocytic leukemia. Blood 2001;98(1):181-186.
Jelinek DF et al., Analysis of clonal B-cell CD38 and immunoglobulin variable region sequence status in relation to clinical outcome for B-chronic lymphocytic leukaemia. Br J Haematol 2001;115(4):854-861.
Jeromin S et al. SF3B1 mutations correlated to cytogenetics and mutations in NOTCH1, FBXW7, MYD88, XPO1 and TP53 in 1160 untreated CLL patients. Leukemia 2014;28(1):108-117.Jeromin S et al. Differences in prognosis of stereotyped IGHV3-21 chronic lymphocytic leukaemia according to additional molecular and cytogenetic aberrations. Leukemia 2016;30(11):2251-2253.
The International CLL-IPI working group. An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta.analysis of individual patient data. Lancet Oncol 2016;17:779-790.
Kovacs et al. Minimal residual disease assessment improves prediction of outcome in patients with chronic lymphocytic leukemia (CLL) who achieve partial response: comprehensive analysis oft wo phase III studies of the German CLL Study Group. J Clin Oncol. 2016;34(31):3758-3765.
Kröber A et al. V(H) mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood 2002;100(4):1410-1416.
Landau et al. Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell 2013;152: 714–726.
Matutes E et al. The immunological profile of B-cell disorders and proposal of a scoring system for the diagnosis of CLL. Leukemia 1994;8(10):1640-1645.
Messmer BT et al. Multiple distinct sets of stereotyped antigen receptors indicate a role for antigen in promoting chronic lymphocytic leukemia. J Exp Med.2004;200(4):519-525.
Moreau EJ et al. Improvement oft he chronic lymphocytic leukemia scoring system with the monoclonal antibody SN8 (CD79b). Am J Clin Pathol 1997;108(4):378-382.
National comprehensive cancer network (NCCN) Guidelines: CLL 2019
Onkopedia Leitlinie CLL; DGHO April 2019, www.onkopedia.com/de/onkopedia/guidelines/chronische-lymphatische-leukaemie-cll/@@guideline/html/index.html
O’Brien SM et al. A phase 2 study of idelalisib plus rituximab in treatment-naïve older patients with chronic lymphocytic leukemia. Blood 2015;126(25):2686-2694.
O’Brien SM et al. Single-agent Ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: A 5-year experience. Blood 2018;131(17):1910-1919.
Oscier D et al. Prognostic factors identified three risk groups in the LRF CLL4 trial, independent of treatment allocation. Haematologica 201;95:1705-1712.
Oscier DG et al.The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial. Blood 2013; 121(3):468-475.
Rigolin et GM al. Chromosome aberrations detected by conventional karyotyping using novel mitogens in chronic lymphocytic leukemia with "normal" FISH: correlations with clinicobiologic parameters. Blood 2012;119(10):2310-2313.
Roberts AW et al. Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. NEJM 2016;374(4):311-322.
Rossi D et al. Clinical impact of small TP53 mutated subclones in chronic lymphocytic leukemia. Blood 2014;123: 2139–2147.
Rossi D et al. Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia. Blood 2013;121:1403-1412.
S3-Leitlinie Chronische Lymphatische Leukämie (CLL), http://www.leitlinienprogramm-onkologie.de/leitlinien/chronische-lymphatische-leukaemie-cll/
Shanafelt et al. Prospective evaluation of clonal evolution during longterm follow-up of patients with untreated early-stage chronic lymphocytic leukemia. J Clin Oncol. 2006;24(28):4634-4641.
Skowronska et al. Biallelic ATM inactivation significantly reduces survival in patients treated on the United Kingdom Leukemia Research Fund Chronic Lymphocytic Leukemia 4 trial. J Clin Oncol 2012;30(36):4524-4532.
Stamatopoulos K et al. Antigen receptor stereotypy in chronic lymphocytic leukemia. Leukemia 2017;31(2):282-291.
Stengel A et al. The impact of TP53 mutations and TP53 deletions on survival varies between AML, ALL, MDS and CLL: an analysis of 3307 cases. Leukemia 2017;31(3):705-711.
Stilgenbauer S et al. Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood 2014;123(21):3247-3254.
Stilgenbauer S et al. Genetics of chronic lymphocytic leukemia: genomic aberrations and V(H) gene mutation status in pathogenesis and clinical course. Leukemia 2002;16(6):993-1007
Swerdlow SH et al. WHO classification of tumours of haematopoetic and lymphoid tissue. International Agency of Research on Cancer 2017; 4. überarbeitete Version.
Thompson PA et al. Complex karyotype is a stronger predictor than del(17p) for inferior outcome in relapsed or refractory CLL patients treated with Ibrutinib-based Regimens. Cancer 2015;121(20):3612-3621.
Thorselius et al. Strikingly homologous immunoglobulin gene rearrangements and poor outcome in VH3-21-using chronic lymphocytic leukemia patients independent of geographic origin and mutational status. Blood 2006;107:2889-2894.
Tobin G et al. Chronic lymphocytic leukemias utilizing the VH3-21 gene display highly restricted Vlambda2-14 gene use and homologous CDR3s: implicating recognition of a common antigen epitope. Blood 2003;101:4952-4957.
Tobin G et al. Subsets with restricted immunoglobulin gene rearrangement features indicate a role for anitgen selection in the development of chronic lymphocytic leukemia. Blood 2004;104(9):2879-2885.
Woyach et al. Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib. NEJM 2014;370(24):2286-2294.
Zenz T et al. TP53 mutation and survival in chronic lymphocytic leukemia. J Clin Oncol. 2010;28(29):4473-4479.