Chronic lymphocytic leukemia
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
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irk-123456789-1398732018-06-22T03:04:25Z Chronic lymphocytic leukemia Kriachok, I.A. Conference reports 2012 Article Chronic lymphocytic leukemia / I.A. Kriachok // Experimental Oncology. — 2012. — Т. 34, № 4. — С. 378-380. — Бібліогр.: 18 назв. — англ. 1812-9269 http://dspace.nbuv.gov.ua/handle/123456789/139873 en Experimental Oncology Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Conference reports Conference reports |
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Conference reports Conference reports Kriachok, I.A. Chronic lymphocytic leukemia Experimental Oncology |
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Article |
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Kriachok, I.A. |
| author_facet |
Kriachok, I.A. |
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Kriachok, I.A. |
| title |
Chronic lymphocytic leukemia |
| title_short |
Chronic lymphocytic leukemia |
| title_full |
Chronic lymphocytic leukemia |
| title_fullStr |
Chronic lymphocytic leukemia |
| title_full_unstemmed |
Chronic lymphocytic leukemia |
| title_sort |
chronic lymphocytic leukemia |
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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2012 |
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Conference reports |
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http://dspace.nbuv.gov.ua/handle/123456789/139873 |
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Chronic lymphocytic leukemia / I.A. Kriachok // Experimental Oncology. — 2012. — Т. 34, № 4. — С. 378-380. — Бібліогр.: 18 назв. — англ. |
| series |
Experimental Oncology |
| work_keys_str_mv |
AT kriachokia chroniclymphocyticleukemia |
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2025-07-10T09:17:12Z |
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2025-07-10T09:17:12Z |
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1837250940809248768 |
| fulltext |
��� Experimental Oncology ��� �������� ���� ��ecem�er�
in peripheral �lood and �one marrow of some patients
with non-Hodgkin’s lymphomas.
In �99�� the Reference La�oratory was set up as a pu�-
lic service on the �asis of the Immunocytochemistry
�epartment of R.E. Kavetsky Institute of Experimental
Pathology� Oncology and Radio�io logy� National Acad-
emy of Sciences of Ukraine with the aim of the precise
diagnosis of the haematopoietic malignancies �ased
on cytomorphology� cytoche mistry� immunophenotyping
and the techniques of molecular �iology in accordance
with FAB� WHO� EGIL� IC�-�� and IC�-O-� classifications.
The diagnostic activity of the Reference La�oratory covers
�5-�5% of all Ukrainian patients with acute leukemias�
chronic lymphoid and myeloid leukemias� myelodysplastic
syndromes� malignant lymphomas� histiocytosis� and
metastatic lesions of lymph nodes and �one marrow.
At present� the patients with tumors of haematopoietic and
lymphoid tissues are diagnosed according to up-to-date
WHO classification. We �elieve that only precise diagnosis
of the major types of hematological malignancies to the
up-to-date classification with delineation of the specific
�iological su�types of hematological malignancies may
represent the �asis for further molecular �iological and
epidemiological studies. New insight into the �iology of the
lymphoid malignancies in the coming years might well
improve our a�ility to evaluate patients and chose therapy.
REFERENCES
1. Ferry YA, Harris NL. Atlas of lymphoid hyperplasia
and lymphoma. Philadelphia: W.B. Saunders Co., 1997. 273 p.
2. Human lymphoma: clinical implications of the REAL
classification. D.Y. Mason, N.L. Harris (eds.). London
etc.: Springer-Verlag, 1999. 554 p.
3. World Health Organization classification of tumours.
Pathology and genetics of tumours of haematopoietic and lym-
phoid tissues. E.S. Jaffe, N.L. Harris, H. Stein, Y.W. Vardiman
(eds.). Lyon: IARC Press, 2001. 351 p.
4. Feller AC, Diebold J. Histopathology of nodal and
extranodal non-Hodgkin lymphoma. Berlin etc.: Springer-
Verlag, 2004. 464 p.
5. The lymphomas, 2nd ed. G.P. Canellos T.A. Lister,
B. Young (eds). Philadelphia: Elsevier Inc., 2006. 581 p.
6. WHO classification of tumours of haematopoietic and
lymphoid tissues. S.H. Swerdlow, E. Campo, N.L. Harris,
E.S. Jaffe, S.A. Pileri, H. Stein, J. Thiele, J.W. Vardiman
(eds.). Lyon: IARC Press, 2008. 439 p.
7. Gluzman DF, Sklyarenko LM, Nadgornaya VA. Tu-
mours of haematopoietic and lymphoid tissues (cytomor-
phology, immunocytochemistry, diagnostic algorithms).
Kyiv: DIA, 2008. 193 p. (in Russian)
8. Gluzman DF, Sklyarenko LM, Nadgornaya VA. Diag-
nostic oncohaematology. Kyiv: DIA, 2011. 256 p. (in Russian).
CHRONIC LYMPHOCYTIC LEUKEMIA
I.A. Kriachok
Oncohematology Department, National Cancer
Institute, Kyiv, Ukraine
Correspondence: irina.kryachok@unci.org.ua
Chronic lymphocytic leukemia �CLL� is the most com-
mon form of leukemia in Western countries with an inci-
dence of �.�/�������/year [�]. The incidence increases
to >��/�������/year at an age of >�� years. The median
age at diagnosis is �� years. A�out ��% of CLL patients
are reported to �e younger than 55 years.
The guidelines for the diagnosis and treatment
of chronic lymphocytic leukemia were revised �y the
International Workshop on CLL in ���� �IWCLL�. Crite-
ria for CLL are as follows: the presence in the peripheral
�lood of 5 x ��9/L monoclonal B lymphocytes for the
at least � months. The clonality of the circulating B lym-
phocytes needs to �e confirmed �y flow cyto metry [�].
Typical immunophenotype of CLL lymphocyte is C�5+�
C���+� C���+/-� C���-� C��9+� C��� dim� slgdim+ and
cyclin �I� [�]. Bone marrow examination is not required
for diagnosis and a CT scan not required for staging�
�ut flow cytometry is crucial for correct diagnosis.
The first prognostic marker to �e used in the
clinical management of CLL was the Rai clinical stag-
ing system� pu�lished in �9�5 [�]. This system was
later followed �y the Binet staging system� pu�lished
in �9�� [5]. Both of these staging systems provide
a �asic framework for estimating prognosis and are
factored into the current International Workshop
on CLL guidelines for initiation of treatment [�].
Multiple factors� measured in standard clinical la�-
oratory tests� affect the clinical course of CLL. These
factors include lymphocyte count� lymphocyte dou-
�ling time� M level� sTK level� angiopoietin-� �Ang-��
level� and solu�le cluster designation markers �C����
C���� and C��9d�. Other clinical markers that have
�een investigated as potential prognostic indicators
include age� gender [6]� lymphocyte dou�ling time [�]�
num�er of prolymphocytes [�]� pattern of �one mar-
row involvement and percentage of smudge cells [9].
Approximately ��% of individuals with CLL have
acquired chromosomal a�normalities within their
malignant clone and can �e categorized into five
prognostic groups accordingly: deletion ��q �median
survival� ��� months�; deletion ��q �median survival�
�9 months�; trisomy �� �median survival� ��� months�;
normal cytogenetics �median survival� ��� months�;
and deletion ��p �median survival� �� months�. Re-
ciprocal chromosome translocations are descri�ed
�ut are rare in CLL. A complex cytogenetic karyotype
can �e identified in ~I6% of patients and is commonly
associated with poor prognostic features including
C��� expression and unmutated IgHV [��].
The outcome of patients with leukemic cells that use
an unmutated IgVH gene is inferior to those patients with
leukemic cells that use a mutated IgVH gene. In addi-
tion� the VH�.�� gene usage is an unfavora�le prognos-
tic marker independent of the IgVH mutational status.
Leukemic cell expression of ZAP-�� and C��� was
found to correlate with the expression of unmutated
IgVH genes and to predict a poor prognosis.
However� the association �etween expression of ZAP-
�� or C��� with the expression of unmutated IgVH genes
is not a�solute. It is uncertain whether leukemia-cell
expression of unmutated IgVH genes or ZAP-�� pre-
dict the response to treatment or overall survival� once
therapy is required. Taken together� further clinical trials
are needed to standardize the assessment of these pa-
Experimental Oncology ��� �������� ���� ��ecem�er���� �������� ���� ��ecem�er� ��ecem�er� ��9
rameters and to determine whether they should affect
the management of patients with CLL [�].
Recently 9 significantly mutated genes were identi-
fied that occurred in 5 core signaling pathways in which
the genes play esta�lished roles: �NA damage repair
and cell-cycle control �TP53, ATM�� Notch signaling
�FBXW7, NOTCH I�� inflammatory pathways �MYD88,
DDX3X, MAPKI�� and RNA splicing/processing �SF3BI,
DDX3X�. Of these mutations� 5 of the mutated genes
have �een implicated in CLL for the first time [��].
Treatment of CLL ranges from periodic o�servation
with treatment of infectious� hemorrhagic� or immuno-
logic complications to a variety of therapeutic options�
including steroids� alkylating agents� purine analogs�
com�ination chemotherapy� monoclonal anti�odies�
and transplant options [��]. A meta analysis of rando-
mized trials showed no survival �enefit for immediate
versus delayed therapy for patients with early stage
disease� nor for the use of com�ination regimens
incorporating an anthracycline compared with a single-
agent alkylator for advanced stage disease.
Indication for start of treatment are as follows: Binet
stage C� Rai stages III or IV� Binet stage B or Rai stages
I or II� with at least one of: splenomegaly� and or lymph-
adenopathy� when symptomatic� progressive� or massive
�> 5 cm spleen� �� cm nodes� progressive lymphocytosis
�increase > 5�% in � months or Lymphocyte �ou�ling
Time < 6 months� AIHA or ITP unresponsive to cortico-
steroids� disease-related symptom �i.e.� weight loss�
significant fatigue� fever�. Biological markers �e.g. cyto-
genetics� C���� ZAP-��� IGVH mutations� are not an in-
dication to start therapy �outside clinical trials�. Response
to therapy is the most important prognostic factor.
Recently su�stantial advances have �een made in the
treatment of CLL patients� most of which relate to mono-
clonal anti�odies �MA�� alone and in com�ination with
various chemotherapeutic drug com�inations. Preferred
treatment of choice �for patients with good performance
status� is the com�ination of rituxima� with fludara�ine
and cyclophosphamide �R-FC�. Phase � clinical studies
demonstrated that R-FC is the most effective com�ina-
tion to date in terms of achieving CR in CLL in previously
untreated [��] and treated [��] patients.
Allogeneic stem cell transplant has �een found
to induce long-term disease-free survival in CLL pa-
tients with deletion ��p [�5]. However� given the age
of diagnosis and frequent presence of co-mor�idities�
transplant is not often an option for these patients. This
has led to a search for non-p5� dependent agents for
use in the management of CLL with deletion ��p.
Alemtuzuma�� on the other hand� appears to work
via a p5� independent pathway� and has demonstrated
efficacy in ��p deleted or p5� mutated CLL [�6]. Less
effective for �ulky �5 cm�. ��p- patients who present with
�ulky lymphadenopathy remains a therapeutic challenge.
Ofatumuma�� a human C��� Ma� that �inds
to another C��� epitope� has shown promising results
when used as a single agent in refractory CLL patients
OR rate of approx 5�% with a significantly longer sur-
vival in responding patients [��]. Several other MA�s
are in early clinical testing or in the pipeline. In addi-
tion� a growing num�er of small molecules are �eing
explored in clinical trials� providing hope for the future
that CLL will �e transformed into a disease that may
�e kept under control for very long periods of time.
For the selection of second-line treatment� the qual-
ity of first response plays a major role — if physically
fit patients with refractory disease or relapse within
�� months after chemoimmunotherapy — or fludara-
�ine-�ased com�ination therapy� the second remis-
sion should �e used to proceed to an allogeneic stem
cell transplant �especially indicated in very high risk
[del�l�p�� p5� mutation] and/or refractory disease [��].
If the patient is physically unfit� the treatment
should �e changed to an alternative regimen. The
prognosis in this group is usually poor. If relapse is later
than �� months after the first therapy� the first-line
therapy should �e repeated.
O�limersen is a drug that has �een studied for use
in CLL. An immunotoxin known as BL�� has shown
a great deal of promise in treating hairy cell leukemia
�HCL� in clinical trials. A newer version of this drug� known
as HA�� �CAT-���5� is now �eing tested for use against
CLL. The Bruton’s tyrosine kinase �BTK� inhi�itor PCI
���65 �under development �y Pharmacyclics� showed
high rates of progression-free survival and low toxicity
in patients with relapsed CLL� according to data presented
here at American Society of Hematology �ASH� 5�rd An-
nual Meeting. The drug is now in a phase � clinical trial.
REFERENCES
1. SEER Clinical Statistics Review, 1975-2007. S.F. Altek-
ruse, C.L. Kosari, M. Krapcho et al., eds. Bethesda, MD: Na-
tional Cancer Institute, 2010.
2. Hallek M, Cheson BD, Catovsky D, et al. Guidelines
for the diagnosis and treatment of chronic lymphocytic leu-
kemia: a report from the International Workshop on Chronic
Lymphocytic Leukemia updating the National Cancer Institute-
Working Group 1996 guidelines. Blood 2008; 111: 5446–56.
3. Moreau EJ, Matutes E, A’Hern RP, et al. Improvement
of the chronic lymphocytic leukemia scoring system with the
monoclonal antibody SN8 (CD79b). Am J Clin Pathol 1997;
108: 378–82.
4. Rai KR, Sawitsky A, Cronkite EP, Chanana AD, et al.
Clinical staging of chronic lymphocytic leukemia. Blood 1975;
46: 219–34.
5. Binet JL, Auquier A, Dighiero G, et al. A new prognostic
classification of chronic lymphocytic leukemia derived from
a multivariate survival analysis. Cancer 1981; 48: 198–206.
6. Catovsky D, Fooks J, Richards S. Prognostic factors
in chronic lymphocytic leukaemia: the importance of age, sex
and response to treatment in survival. A report from the MRC
CLL I trial. MRC Working Party on Leukaemia in Adults.
Br J Haematol 1989; 72: 141–9.
7. Molica S, Alberti A. Prognostic value of the lymphocyte
doubling time in chronic lymphocytic leukemia. Cancer 1987,
60: 2712–6.
8. Melo JV, Hegde U, Parreira A, et al. Splenic B cell
lymphoma with circulating villous lymphocytes: differential
diagnosis of B cell leukaemias with large spleens. J Clin Pathol
1987; 40: 642–51.
9. Johansson P, Eisele L, Klein-Hitpass L, et al. Percentage
of smudge cells determined on routine blood smears is a novel
��� Experimental Oncology ��� �������� ���� ��ecem�er�
prognostic factor in chronic lymphocytic leukemia. Leuk Res
2010; 34: 892–8.
10. Haferlach C, Dicker F, Schnittger S, 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: 2442–51.
11. Wang L, Lawrence MS, Wan Y et al. SF3BI and other
novel cancer genes in chronic lymphocytic leukemia. N Engl
J Med 2011; 365: 2497–506.
12. Gribben JG, O’Brien S. Update on therapy of chronic
lymphocytic leukemia. J Clin Oncol 2011; 29: 544–50.
13. Tarn CS, O’Brien S, Wierda W, et al. Long-term
results of the fludarabine, cyclophosphamide, and rituximab
regimen as initial therapy of chronic lymphocytic leukemia.
Blood 2008; 112: 975–80.
14. Wierda W, O’Brien S, Wen S, et al. Chemoimmuno-
therapy with fludarabine, cyclophosphamide, and rituximab
for relapsed and refractory chronic lymphocytic leukemia.
J Clin Oncol 2005; 23: 4070–8.
15. Schetelig J, Biezen van A, Brand R, et al. Allogeneic
hematopoietic stem-cell transplantation for chronic lympho-
cytic leukemia with I7p deletion: a retrospective European
Group for Blood and Marrow Transplantation analysis. J Clin
Oncol 2008; 26: 5094–100.
16. Stilgenbauer S, Zenz T, Winkler D, et al. Subcutaneous
alemtuzumab in fludarabine-refractory chronic lymphocytic
leukemia: clinical results and prognostic marker analyses from
the CLL2H study of the German Chronic Lymphocytic
Leukemia Study Group. J Clin Oncol 2009; 27: 3994–4001.
17. Wierda WG, Chiorazzi N, Dearden C, et al. Chronic
lymphocytic leukemia: new concepts for future therapy. Clin
Lymphoma Myeloma Leuk 2010; 10: 369–78.
18. Dreger P, Corradini P, Kimby E, et al. Indications for
allogenic stem cell transplantation in chronic lymphocytic leu-
kemia: EBMT transplant consensus Leukemia 2007; 21: 12–17.
FOLLICULAR LYMPHOMA
F. De Angelis, R. Foà
Hematology Division, Department of Cellular
Biotechnologies and Hematology, Univerity
of Rome “Sapienza”, Rome, Italy
Correspondence: rfoa@bce.uniroma1.it
Follicular lymphoma �FL� is the second most com-
mon type of non-Hodgkin lymphoma �NHL� in Western
Countries� accounting for ��% of all NHL and for ��%
of all indolent forms� with a median age at diagnosis
of a�out 6� years [���]. Before the advent of chemo-
therapy� the majority of patients with FL died within
5 years. With the current therapies� the expected me-
dian survival is approximately ���� years [�]. A�out �5%
of FL cases have a specific translocation t���;��� that
leads to the overexpression of the BCL� protein� a mem-
�er of a family of anti-apoptotic proteins� although other
genetic alterations may �e detected in this su�type
of lymphoma. As defined �y the WHO� FLs are charac-
terized �y a follicular growth pattern including centro-
cytes �small- to medium-sized cells� and centro�lasts
�large cells�� and are graded from I to III according to the
amount of centro�lasts present. The clinical aggressive-
ness of the tumor increases with an increasing num�ers
of centro�lasts. Grade I is defined �y ≥5 centro�lasts/
high power field �hpf� �follicular small cleaved�� Grade
II �y 6 to �5 centro�lasts/hpf �follicular mixed�� Grade III
�y more than �5 centro�lasts/hpf �follicular large cell�.
Grade III has �een su�divided into Grade IIIa� in which
centrocytes are present and Grade III�� in which there
are sheets of centro�lasts. Grade from I to IIIa are
considered as indolent NHL su�types� while grade III�
�ehaves as an aggressive lymphoma and is treated
similarly to a diffuse large B-cell lymphoma [5]. Bone
marrow involvement is very common �a�out ��% of all
cases� with paratra�ecular lymphoid aggregates� al-
though other organ involvement is uncommon. FL cells
express monoclonal immunoglo�ulin �Ig� light chains;
they are C��9+� C���+� C���+� C���+ and BCL�+� while
they are negative for C�5 and C���. Clonal Ig gene
rearrangements are also present and most cases have
extensive somatic mutations.
In recent decades� the introduction of several treat-
ment options �single alkylating agents� com�ination
chemotherapy with or without doxoru�icin or fludara�ine�
total lymphoid irradiation� has improved the overall survival
�OS� for patients with FL� with complete remission rates
ranging from 65 to �5% [6]. Fisher et al. demonstrated that
the introduction of the anti-C��� monoclonal anti�ody
Rituxima� significantly improved OS [�]. The prognosis
of FL at diagnosis is currently evaluated on the �asis
of specific indexes: the Follicular Lymphoma International
Prognostic Index �FLIPI� considers five prognostic factors�
including patient age� stage� num�er of involved nodal ar-
eas� serum lactate dehydrogenase and hemoglo�in level
[�]. It was developed through an international retrospec-
tive study of survival data on ��6� patients with FL diag-
nosed �etween �9�5 and �99�. Currently� FLIPI is a widely
accepted tool for risk assessment of FL. However� the FLIPI
has �een designed prior to the era of anti-C��� monoclo-
nal anti�odies and the initial cohort does not represent the
present course of the disease. More recently� a modified
version of this scoring system� the FLIPI-�� was proposed
�y Federico et al. [9] on the �asis of the F� study� in which
��9� patients �etween January ���� and May ���5 with
a newly diagnosed FL were registered and 9�� individuals
receiving treatment were selected as the study popula-
tion. This new prognostic score has� as a target end point�
progression-free survival �PFS�� considered more realistic
than OS for a type of lymphoma with a median survival
likelihood of �� years.
Treatment options are stage-related: while dis-
seminated FL is considered an incura�le disease� with
a trend to relapse� localized stage FL potentially has
a different clinical outcome. In fact� it has �een dem-
onstrated that in 5�% of cases it is possi�le to o�tain
a definitive eradication of the disease. According to the
current guidelines [��� ��]� stage I�II disease should not
�e managed with a frontline strategy of watchful waiting�
radiation therapy representing the gold standard for this
group of patients: a radiation dose of �� to �6 Gy deliv-
ered in �5 to �� fractions over ��� weeks is associated
with local control rates of more than 95%. �espite the
limited stage� BCL2/IgH+ positive cells could �e found
at diagnosis in the peripheral �lood and/or �one marrow
of �6 of �� patients �66.6%� �y quantitative PCR and
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