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Curr Hematol Malig Rep

DOI 10.1007/s11899-015-0294-x

CHRONIC LYMPHOCYTIC LEUKEMIAS (N JAIN, SECTION EDITOR)

Prognostic Factors for Chronic Lymphocytic Leukemia


Christopher Chen 1 & Soham Puvvada 2

# Springer Science+Business Media New York 2016

Abstract As novel strategies for treatment and prognosti- times. Indeed, despite the name of the disease, certain popu-
cation of chronic lymphocytic leukemia (CLL) evolve, the lations of patients have median survival times of as little as
traditional Rai and Binet systems can now be updated with 29 months [1]. Thus, there have been numerous efforts to
more modern prognostic markers. This is a review of the guide clinicians to more accurately prognosticate this disease.
latest articles which combine studies from major CLL cen- Historically, Binet and Rai have been the two staging sys-
ters to summarize major prognostic factors for patients tems used to estimate prognosis of disease. The Binet system
diagnosed with CLL. The prognostic information can be grouped patients into three categories: A, B, and C [2]. Stages
categorized into three categories: genetic abnormalities A and B both have hemoglobin count of ≥10 g/dL and platelet
which include 17p, 11q, and immunoglobulin heavy chain count of ≥100/L, but differ in characterization of lymphade-
variable (IGHV) abnormalities; biochemical abnormalities nopathy; stage A has <3 enlarged areas, whereas stage B has
and cell surface markers which include serum thymidine ≥3 enlarged areas. Stage C is characterized by hemoglobin
kinase, β-2-microglobulin, CD49d, CD38, and ZAP-70 count of <10 g/dL and platelet count of <100,000/mm3 irre-
levels; and patient characteristics which include sex, age, spective of lymphadenopathy. The median survival for stage
and performance status. A is 8.5–9 years, stage B is 5–6 years, and stage C is 1.5 years.
The original Rai staging system was a five-stage system
Keywords Chronic lymphocytic leukemia . Treatment . that was later simplified into the modified Rai staging system,
Prognostication where the disease is categorized into three subgroups: low,
intermediate, and high [3, 4]. Low stage disease is character-
ized with lymphocytosis and absolute lymphocyte count
Introduction and Background >15 × 109/L. Intermediate stage disease in addition to lympho-
cytosis includes lymphadenopathy, hepatomegaly, and
Chronic lymphocytic leukemia is a biologically heteroge- splenomegaly. High stage disease is characterized by anemia
neous disease. This molecular heterogeneity is associated with (Hb ≤ 11 g/dL) or thrombocytopenia (platelets ≤ 100 × 109/L).
a wide range of progression-free survival and overall survival Low stage disease has median survival of >10 years, interme-
diate stage disease 7 years, and high stage disease 1.5 years.
This article is part of the Topical Collection on Chronic Lymphocytic
Leukemias

Prognostic Factors and Markers


* Christopher Chen
cmchen@email.arizona.edu
With the advent of molecular genetics and novel drugs that
* Soham Puvvada
SPuvvada@uacc.arizona.edu
target specific abnormalities, Binet and Rai staging sys-
tems are not adequate to comprehensively characterize
prognostic stratification in chronic lymphocytic leukemia
1
1515 N Campbell Ave., Tucson, AZ 85724, USA (CLL). An Italian study reviewed a cohort of 212 patients
2
1515 N Campbell Ave., Tucson, AZ 85719, USA in which cytogenetic lesions, IGHV mutational status, and
Curr Hematol Malig Rep

CD38 expression data were used to create the Integrated cancer types [14–16]. In relation to CLL, it has been shown to
CLL Scoring System [5••]. Another study performed on a have a tremendous impact on multiple studies, including
larger cohort of 1223 treatment-naive patients from the Ger- poorer overall survival, decreased response to standard che-
man CLL Study Group (GCLLSG) dataset identified eight motherapeutic regiments, and high hazard ratios in terms of
independent predictors of overall survival which were then prognostic factors [17–19]. However, targeted agents such as
validated in an independent cohort of patients from a cohort ibrutinib, an oral inhibitor of BTK that has tremendous activ-
of 676 newly diagnosed CLL patients at the Mayo Clinic ity for patients with 17p deletion, are now current standard
[6••]. All of the eight independent predictors have previously first-line therapy for patients with 17p deletion [20]. Although
been confirmed by other publications as prognostic markers TP53 is located on 17p, it is not always a direct relationship
for CLL, but this study took into account potential confound- between 17p deletion and p53 mutation; in a study of 308
ing factors in its statistical analysis, minimizing associations consecutive untreated CLL patients, 44 patients (23 %) were
without true prognostic implications. Using the hazard ratio found to have TP53 disruption by either mutation or deletion.
for the eight factors, the GCLLSG proposed a new prognostic TP53 mutation was found in 31 patients of whom 10 patients
score table (Table 1). did not have 17p deletion, and 13 patients had 17p deletion
The eight independent predictors from the GCLLSG in- without p53 mutation. This study emphasizes that TP53 mu-
clude the following: sex, age, ECOG status [7], del(17p), tations, regardless of 17p deletion status, are a major indepen-
del(11q), IGHV mutation status, serum β2-microglobulin, dent predictor of shorter survival and poor response to chemo-
and serum thymidine kinase (s-tk). Other factors that have also therapy with a hazard ratio of 3.20 (p = 0.002) [21].
recently been reviewed included CD49d, CD38, and protein Deletion of 11q has also long been known to have poorer
tyrosine kinase 2 (PTK2) expression [8, 9•, 10•, 11]. For the prognosis in CLL, and the gene affected by 11q has been
purposes of discussion, the prognostic indicators will be sep- identified as ATM (ataxia-telangiectasia mutated) [22••, 23].
arated into genetic abnormalities, biochemical abnormalities, The ATM gene is associated with multiple lymphoid ma-
and patient characteristics. lignancies including CLL, mantle cell lymphoma, and T
Minimal residual disease (MRD) can be detected by either cell prolymphocytic leukemia [24, 25]. Del 11q was asso-
flow cytometry (FC) or molecular analyses, with FC having a ciated with a 5-year survival of 75 % and a hazard ratio of
higher sensitivity and specificity (96.5 %) compared to PCR 2.1, and 81 % 5-year survival and hazard ratio of 2.6 in
(77.2 %) [12]. In a sample of 493 patients who were separated another data set [6••].
into categories of low (<10−4), intermediate- (≥10−4 to < 10−2), In a phase 1b-2 study multicenter study, a total of 85 pa-
and high-level (≥ 10−2) groups by FC, many of the variables tients with high-risk disease, including 33 % of whom had 17p
discussed in this chapter including age, β2-microglobulin, deletions and 36 % of whom had del11q deletions, were treat-
thymidine kinase, IGHV status, del 17p, clinical response, ed with ibrutinib. At a median follow-up of 20.9 months, 54
and ECOG performance status were analyzed in a Cox regres- patients (64 %) were still receiving treatment, and 31 (36 %)
sion, which showed MRD as an independent prognostic indi- had discontinued treatment. Of the 31 patients who
cator. The groups of patients who were groups in the low discontinued treatment, 11 of them had disease progression,
MRD category during and after therapy were associated with 7 had adverse events, and 13 had therapies adjusted by their
longer progression-free survival (PFS) and overall survival oncologists [26•]. In a 3-year follow-up, long-duration treat-
(OS; p < 0.0001) [13]. ment with ibrutinib was shown to have improved response
quality and durable remissions, thus providing evidence that
Genetic Abnormalities ibrutinib can be tolerated for an extended period and also
provide extended disease control [27••].
TP53 gene that encodes a tumor suppressor protein p53 is Another genetic prognostic factor for CLL that has proven
located on the short arm of chromosome 17, and the deletion repeatedly to be statistically significant is the mutation status
of 17p has been associated with poor outcomes in multiple of immunoglobulin heavy chain variable (IGHV) region.

Table 1 Factors for poor


prognosis in CLL Factors suggestive of poorer prognosis in CLL

Genetic abnormalities Biochemical abnormalities and cell surface markers Patient characteristics

17p/TP53 deletion or mutation Elevated serum thymidine kinase Age ≥ 60


11q deletion Serum β-2-microglobulin Male sex
Unmutated IGHV CD49d+, CD38+ ECOG ≥ 1
BIRC3, NOTCH1, SF3B1 ZAP-70+
Curr Hematol Malig Rep

IGHV region, where somatic mutation allows for the encoding M between 1.7 and 3.5 mg/L was associated with a hazard
to form antibodies after antigen exposure, was associated with ratio of 2.8 (2.0–3.0 confidence interval), and for β2-M
a less aggressive form of the disease when mutated [28]. In a ≥3.5 mg/L, the higher hazard ratio increases to 6.5 (4.6–9.3
study of 79 patients, unmutated IGHV status was associated confidence interval) [6••].
with higher likelihood of disease progression (69 vs. 31 %, While the German study did not find statistical significance
p < 0.001), indications for meeting therapy initiation (65 vs. in several of the cell surface markers such as CD49d, CD38,
32 %, p < 0.001), and shorter overall survival (5-year OS 72 or ZAP-70, the trends seen in other studies cannot be
vs. 100 %, p < 0.001) [29]. overlooked in a discussion of prognosis in CLL. Multiple
There has been tremendous recent progress in the detection studies have proven the prognostic value of CD49d, a protein
of molecular markers which can prognosticate CLL disease that mediates cell-cell interaction in CLL, prolonging cell sur-
progression and survival; these include the baculoviral vival and decreasing cell death [38]. ZAP-70, CD38 positivity,
inhibitor-of-apoptosis repeat containing 3 (BIRC3), and IGHV status were studied in a multivariable analysis of
NOTCH1, and splicing factor 3b subunit 1 (SF3B1) genes. 705 patients, which showed ZAP-70 to be the most prominent
BIRC3 was shown to be associated with high-risk disease of the three markers in predicting time to first treatment.
category along with TP53, where the 10-year survival was IGHV or CD38 status did not impact progression of disease
29 %. NOTCH1, hypothesized to be associated with the in ZAP-70-positive patients necessitating earlier treatment; in
leukocyte adhesion cascade in CLL disease development contrast, IGHV and CD38 status was a strong predictor of
[30], and the SF3B1 gene were implicated in that same earlier disease progression in the ZAP-70-negative patient
study to also show an increased risk of disease progression group [39]. In a pooled analysis of 2972 CLL patients, with
and a poor 10-year survival of 37 % compared to the low- CD49d+ defined as patients who had ≥30 % of neoplastic
est risk group of deletion 13q patients, whose 10-year sur- cells expressing CD49d, CD49d+ patients had a decrease in
vival was 69.3 % [31•]. OS at 5 and 10 years of 7 and 23 %, and a decrease in
Protein tyrosine kinase 2 (PTK2) and microRNAs are other treatment-free survival of 26 and 25 %, respectively [9•]. An-
genetic markers of note. An analysis from an international, other multi-center study confirmed the findings, as CD49d+
multicenter, open-label, phase 3 study showed that patients patients had an increased hazard ratio of 2.7 (p < 0.0001) and
with high PTK2 messenger RNA levels pre-treatment derived need for earlier time to first treatment (p < 0.0001) [40].
greater benefit from rituximab to fludarabine and cyclophos- Within this same study, it showed that CD38+ patients,
phamide, with significant improvements in PFS, independent defined as having surface expression ≥20 % CD38 cells vs
of known prognostic factors in a multivariate model. The <20 %, were associated with a 1.9 (p = 0.002) hazard ratio.
PTK2 gene expression in another patient cohort also yielded There is a working hypothesis that CD38 potentiates CD49d-
similar results [32]. Micro RNAs (MirRs) that modulate gene mediated adhesion through the recruitment of proteins in-
expression have also been shown to have a notable impact on volved in the downstream integrin signaling, leading to
CLL prognosis: Changes in the levels of MiR-15a/16-1 and enforced actin polymerization and cell adhesion, thus increas-
MiR-34 affect BCL-2 and p53 activity, impacting the progno- ing the cell survival and decreased cell death effect of CD49d
sis, and also potentially providing potential areas for future [38]. CD38+ as a prognostic factor on its own has also been
therapy [33]. MiR-29 and miR-181 were shown to have an shown to have unfavorable clinical course with a decreased
inverse relationship with T cell leukemia/lymphoma 1 (TCL1) response to chemotherapy, shorter time to initiation of first
oncogene which was correlated with more aggressive lym- treatment, and decreased survival (p < 0.05) [41].
phoma subtypes [34]. Similarly, ZAP-70 positivity cutoff in CLL cells defined as
≥20 % was also shown to have an impact on prognosis, with a
Biochemical Abnormalities and Cell Surface Markers hazard ratio of 2.9 (p = 0.002) [40]. As a corollary to ZAP-70
positivity, ZAP-70 methylation, which in theory would sup-
Thymidine kinases contribute to the synthesis of DNA and press transcription, has been shown to have an impact on
cell division by introducing deoxythymidine into the DNA; prognosis in a study of 295 patients [42]. Low ZAP-70 meth-
however, levels are generally low, and elevated serum thymi- ylation had significantly shortened time to first treatment and
dine kinase (s-tk) levels are associated with earlier disease OS (p < .0001). Higher methylation had a significantly longer
progression and poorer prognosis in CLL [35, 36]. Serum median time to first treatment of 8.0 vs 3.9 years and hazard
β2 microglobulin (β2-M) is a clinically feasible biomarker. ratio of 0.43. However, ZAP-70 methylation and ZAP-70 ex-
In a cohort of 1502 cases, an elevated serum β2-M of pression did not have an absolute correlation in this study, and
>2.0 mg/L was associated with a worse outcome; in a multi- there were some discrepancies where patients with high ZAP-
variate analysis, the β2-M level was associated with a hazard 70 methylation with high ZAP-70 expression. However, for
ratio of 1.217 for each 1 mg/L increase in the β2-M above OS, ZAP-70 methylation was shown to be statistically signif-
2.0 mg/L as a continuous variable [37•]. In the GCLLSG, β2- icant prognostic indicator for CLL [42].
Curr Hematol Malig Rep

Patient Characteristics Idelalisib, a phosphatidylinositol 3-kinase inhibitor, was


successfully combined with rituximab in a double-blind, pla-
Performance status of a patient limits the treatment options cebo-controlled, phase 3 study with good efficacy. The study
due to comorbidities and also has a direct correlation to prog- had to be terminated early as the control group had a median
nosis of CLL. Using the standardized ECOG performance progress-free survival of 5.5 months, and the study group did
status score, the GCLLSG did note a survival disadvantage not meet that endpoint [47•]. Venetoclax, formerly known as
in patients who had ECOG >0. Patients who were aged 60 or ABT-199, an inhibitor of the B cell lymphoma–2 (BCL-2)
above also were noted to have an increased hazard ratio of 1.3. protein that interferes with cell death, theoretically restores
In patients who are less than 65, with less comorbid condi- apoptosis in cancerous cells. In a phase 1b study, rituximab
tions, fludarabine, cyclophosphamide, and rituximab (FCR) was added to Venetoclax therapy in a patient population with
showed superior efficacy when compared to bendamustine relapsed/refractory CLL, achieving an overall response rate of
and rituximab in a study of 547 patients. The complete re- 88 % and a complete response rate of 31 % [48].
sponse rate was 40.7 % with FCR compared to 31.5 % with With the advent of novel therapies, paradigm shifts in the
BR (p = 0.026); however, there were higher rates of severe understanding of CLL biology and treatment, and availability
neutropenia in the FCR arm (87.7 vs 67.8 %, p < 0.001), of new technologies to improve prognostic stratification, this
with more frequent rates of severe infections especially in is an exciting era for CLL. Current treatment studies have
patients aged 65 or above (48.4 vs 26.8 %; p = 0.001) [43]. only scratched the surface of the role of targeted agents in
There was also a higher rate of MRD-negative patients in the treatment of CLL. The impact of newer prognostic
the FCR arm (74.1 and 62.9 %; p = 0.024), which is asso- markers on the age of novel therapies is evolving. As novel
ciated with improved OS [13]. In addition to the study targeted drugs change the therapeutic landscape of CLL,
done on the GCLLSG where male sex was associated with prognostic strategies will continually be needed to revise
a hazard ratio of 1.3 (p = 0.024) [6••], another study as well with the goal of matching treatment strategies to
reviewed the prognostic value of sex in a 1502 patient improved patient outcomes.
population, and male sex was associated with a hazard
ratio of 1.55 (p = 0.001) [37•].
Compliance with Ethical Standards

Conflict of Interest Soham Puvvada reports institutional research


Conclusion and Future Directions funding Genentech, AbbVie, Spectrum, Janssen and Takeda. Advisory
board member to AbbVie (and Pharmacyclics). Travel funding for inves-
tigators meeting Genentech/Roche.
The disease burden-based prognostic systems such as the Christopher Chen declares no potential conflicts of interest.
Rai and Binet systems do not factor in the molecular, bio-
chemical, and patient characteristics. However, the Human and Animal Rights and Informed Consent This article does
GCLLSG incorporates one of the most comprehensive not contain any studies with human or animal subjects performed by any
prognostic scoring systems that have been externally vali- of the authors.
dated. It helps provide therapeutic guidance with timing of
initiating therapy and tailoring a therapeutic regimen. With
CLL being a disease of the elderly, comorbidities and per-
formance status have a large impact on the potential treat- References
ment options for elderly patients, and further studies are
needed to optimize the timing of use of novel targeted Papers of particular interest, published recently, have been
therapeutics in this population [20]. highlighted as:
The ever-changing landscape of treatment with targeted • Of importance
agents has played a tremendous role in prognosis of CLL. •• Of major importance
Targeted agents such as ibrutinib have now been safely com-
bined with traditional immunochemotherapy in a phase Ib 1. Lee JS et al. Prognosis of chronic lymphocytic leukemia: a multi-
variate regression analysis of 325 untreated patients. Blood.
trial. The trial shows no significant increase in toxicity and 1987;69(3):929–36.
remarkable overall response rates of 93 % and progression- 2. Binet JL et al. A new prognostic classification of chronic lympho-
free-survival of 86 and 70 % at 12 and 36 month follow-up cytic leukemia derived from a multivariate survival analysis.
intervals, which now will be followed upon with a phase II Cancer. 1981;48(1):198–206.
study [44••]. In addition, complex karyotype at the time of 3. Rai KR et al. Clinical staging of chronic lymphocytic leukemia.
Blood. 1975;46(2):219–34.
diagnosis [45] and the presence of mutations in BTK and 4. Gale RP, Rai KR. A critical analysis of staging in CLL. Chronic
PLCG2 [46] were also associated with less robust response lymphocytic leukemia: recent progress and future directions. New
to ibrutinib. York: Liss; 1987. p. 253–64.
Curr Hematol Malig Rep

5.•• Visentin A, et al. Integrated CLL scoring system, a new and simple 22.•• Hurtado AM et al. Prognostic signature and clonality pattern of
index to predict time to treatment and overall survival in patients recurrently mutated genes in inactive chronic lymphocytic leuke-
with chronic lymphocytic leukemia. Clin Lymphoma Myeloma mia. Blood Cancer J. 2015;5, e342. Detailed discussion of
Leuk. 2015;15(10):612–620. This is a very recent article with markers which can be detected in asymptomatic early-stage
reviews of multiple factors known to have an effect on prognosis CLL which can provide prognostic information for patients
in CLL. Many of its findings correlate with previous known and clinicians. Reviews mutations of ATM, NOTCH1, TP53,
prognostic factors, but combine it in one population group in and SF3B1.
a well-organized paper. 23. Dohner H et al. 11q deletions identify a new subset of B-cell chron-
6.•• Pflug N et al. Development of a comprehensive prognostic index ic lymphocytic leukemia characterized by extensive nodal involve-
for patients with chronic lymphocytic leukemia. Blood. ment and inferior prognosis. Blood. 1997;89(7):2516–22.
2014;124(1):49–62. This article from the German CLL Study 24. Gumy-Pause F, Wacker P, Sappino AP. ATM gene and lymphoid
Group is one of the most extensive reviews of prognostic factors malignancies. Leukemia. 2004;18(2):238–42.
for CLL with the largest patient sample size. It has information 25. Monni O, Knuutila S. 11q deletions in hematological malignancies.
on the hazard ratios, 5-year survival and also externally con- Leuk Lymphoma. 2001;40(3-4):259–66.
firmed their findings with another patient population from the 26.• Byrd JC et al. Targeting BTK with ibrutinib in relapsed chronic
Mayo Clinic. lymphocytic leukemia. N Engl J Med. 2013;369(1):32–42.
7. Oken MM et al. Toxicity and response criteria of the Eastern Discussion on ibrutinib, a drug that has changed the treatment
Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6): landscape of CLL as it has dramatically improved rates of pa-
649–55. tients achieving durable remissions in patients who had re-
8. Shanafelt TD et al. CD49d expression is an independent predictor lapsed disease with high-risk genetic features.
of overall survival in patients with chronic lymphocytic leukaemia: 27.•• Byrd JC et al. Three-year follow-up of treatment-naive and previ-
a prognostic parameter with therapeutic potential. Br J Haematol. ously treated patients with CLL and SLL receiving single-agent
2008;140(5):537–46. ibrutinib. Blood. 2015;125(16):2497–506. A discussion of the ef-
9.• Bulian P et al. CD49d is the strongest flow cytometry-based pre- ficacy of ibrutinib in a longer term setting, showing durable
dictor of overall survival in chronic lymphocytic leukemia. J Clin responses with modest toxicity profiles.
Oncol. 2014;32(9):897–904. Recent article showing that the use 28. Hamblin TJ et al. Unmutated Ig V(H) genes are associated with a
of flow cytometry results is a good predictor for CLL prognosis. more aggressive form of chronic lymphocytic leukemia. Blood.
10.• Brachtl G et al. The pathogenic relevance of the prognostic markers 1999;94(6):1848–54.
CD38 and CD49d in chronic lymphocytic leukemia. Ann Hematol. 29. Gladstone DE et al. Importance of immunoglobulin heavy chain
2014;93(3):361–74. Recent article discussing the cell surface variable region mutational status in del(13q) chronic lymphocytic
markers that contribute to the prognosis of CLL. leukemia. Leuk Lymphoma. 2011;52(10):1873–81.
11. Damle RN et al. Ig V gene mutation status and CD38 expression as 30. Riches JC et al. Trisomy 12 chronic lymphocytic leukemia cells
novel prognostic indicators in chronic lymphocytic leukemia. exhibit upregulation of integrin signaling that is modulated by
Blood. 1999;94(6):1840–7. NOTCH1 mutations. Blood. 2014;123(26):4101–10.
12. Raponi S et al. Minimal residual disease monitoring in chronic 31.• Rossi D et al. Integrated mutational and cytogenetic analysis iden-
lymphocytic leukaemia patients. A comparative analysis of flow tifies new prognostic subgroups in chronic lymphocytic leukemia.
cytometry and ASO IgH RQ-PCR. Br J Haematol. 2014;166(3): Blood. 2013;121(8):1403–12. A review of known mutational and
360–8. cytogenetic factors that affect CLL prognosis, which groups the
13. Bottcher S et al. Minimal residual disease quantification is an inde- mutations into high-risk, intermediate-risk, low-risk, and very
pendent predictor of progression-free and overall survival in chron- low-risk categories.
ic lymphocytic leukemia: a multivariate analysis from the random- 32. Weisser M et al. PTK2 expression and immunochemotherapy out-
ized GCLLSG CLL8 trial. J Clin Oncol. 2012;30(9):980–8. come in chronic lymphocytic leukemia. Blood. 2014;124(3):420–5.
14. Matlashewski G et al. Isolation and characterization of a human p53 33. Balatti V, Pekarky Y, Croce CM. Role of microRNA in chronic
cDNA clone: expression of the human p53 gene. EMBO J. lymphocytic leukemia onset and progression. J Hematol Oncol.
1984;3(13):3257–62. 2015;8(1):12.
15. Isobe M et al. Localization of gene for human p53 tumour antigen 34. Pekarsky Y et al. Tcl1 expression in chronic lymphocytic leukemia
to band 17p13. Nature. 1986;320(6057):84–5. is regulated by miR-29 and miR-181. Cancer Res. 2006;66(24):
16. McBride OW, Merry D, Givol D. The gene for human p53 cellular 11590–3.
tumor antigen is located on chromosome 17 short arm (17p13). 35. Hallek M et al. Elevated serum thymidine kinase levels identify a
Proc Natl Acad Sci U S A. 1986;83(1):130–4. subgroup at high risk of disease progression in early,
17. Dohner H et al. Genomic aberrations and survival in chronic lym- nonsmoldering chronic lymphocytic leukemia. Blood. 1999;93(5):
phocytic leukemia. N Engl J Med. 2000;343(26):1910–6. 1732–7.
18. Tam CS et al. Long-term results of the fludarabine, cyclophospha- 36. Konoplev SN et al. High serum thymidine kinase 1 level predicts
mide, and rituximab regimen as initial therapy of chronic lympho- poorer survival in patients with chronic lymphocytic leukemia. Am
cytic leukemia. Blood. 2008;112(4):975–80. J Clin Pathol. 2010;134(3):472–7.
19. Fischer K et al. Bendamustine in combination with rituximab for 37.• Gentile M et al. Italian external and multicentric validation of the
previously untreated patients with chronic lymphocytic leukemia: a MD Anderson Cancer Center nomogram and prognostic index for
multicenter phase II trial of the German Chronic Lymphocytic chronic lymphocytic leukaemia patients: analysis of 1502 cases. Br
Leukemia Study Group. J Clin Oncol. 2012;30(26):3209–16. J Haematol. 2014;167(2):224–32. Another recent review of fac-
20. Jain N, O’Brien S. Initial treatment of CLL: integrating biology and tors that affect CLL prognosis in a statistical analysis of patients
functional status. Blood. 2015;126(4):463–70. in 1502 CLL cases, validating a Prognostic Index proposed by
21. Rossi D et al. The prognostic value of TP53 mutations in chronic MD Anderson cancer Center.
lymphocytic leukemia is independent of Del17p13: implications for 38. Dal Bo M et al. Microenvironmental interactions in chronic lym-
overall survival and chemorefractoriness. Clin Cancer Res. phocytic leukemia: the master role of CD49d. Semin Hematol.
2009;15(3):995–1004. 2014;51(3):168–76.
Curr Hematol Malig Rep

39. Rassenti LZ et al. Relative value of ZAP-70, CD38, and immuno- leukemia. Blood. 2015;125(19):2915–22. Very recent phase 1b
globulin mutation status in predicting aggressive disease in chronic study that shows benefit of combining ibrutinib and
lymphocytic leukemia. Blood. 2008;112(5):1923–30. chemoimmunotherapy with very promising results.
40. Majid A et al. CD49d is an independent prognostic marker that is 45. Thompson PA et al. Complex karyotype is a stronger predictor than
associated with CXCR4 expression in CLL. Leuk Res. 2011;35(6): del(17p) for an inferior outcome in relapsed or refractory chronic
750–6. lymphocytic leukemia patients treated with ibrutinib-based regi-
41. Durig J et al. CD38 expression is an important prognostic marker in mens. Cancer. 2015;121(20):3612–21.
chronic lymphocytic leukaemia. Leukemia. 2002;16(1):30–5. 46. Maddocks KJ et al. Etiology of ibrutinib therapy discontinuation
42. Claus R et al. Validation of ZAP-70 methylation and its relative and outcomes in patients with chronic lymphocytic leukemia.
significance in predicting outcome in chronic lymphocytic leuke- JAMA Oncol. 2015;1(1):80–7.
mia. Blood. 2014;124(1):42–8. 47.• Furman RR et al. Idelalisib and rituximab in relapsed chronic lym-
43. Eichhorst B, Fink AM, Busch R, et al. Frontline phocytic leukemia. N Engl J Med. 2014;370(11):997–1007.
chemoimmunotherapy with fludarabine, cyclophosphamide, and Double-blind, placebo-controlled phase 3 study that showed ef-
rituximab (FCR) shows superior efficacy in comparison to ficacy of idelalisib used in combination with rituximab in pa-
bendamustine and rituximab (BR) in previously untreated and tients which improved progression-free survival, response rate,
physically fit patients with advanced chronic lymphocytic leuke- and overall survival among patients with relapsed CLL less
mia (CLL): final analysis of an international, randomized study of able to undergo chemotherapy.
the German CLL Study Group (GCLLSG) (CLL10 Study). 48. Roberts AW, Ma S, Brander DM, et al. Determination of the rec-
American Society of Hematology (ASH) Annual Meeting. ommended phase 2 dose of ABT-199 combined with rituximab in
December 6-9, 2014; San Francisco, CA. Abstract 19, 2014. patients with relapsed/refractory chronic lymphocytic leukemia.
44.•• Brown JR et al. The Bruton tyrosine kinase inhibitor ibrutinib with 2014 ASH Annual Meeting. Abstract 325. Presented December 8,
chemoimmunotherapy in patients with chronic lymphocytic 2014., 2014.

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