[CHRONIC LYMPHOCYTIC LEUKEMIA, BLOOD].

B-cell chronic
lymphocytic leukemia is the most common chronic leukemia in
adults in Western countries. Most cases involve blood and bone
marrow with or without involvement of lymph nodes, spleen, liver,
and other organs. The neoplastic lymphocytes are small but slightly
larger than normal small lymphocytes and show scant cytoplasm and
round to slightly irregular nuclei containing clumped chromatin
(three arrows). Nucleoli are small to indistinct. A characteristic
morphologic feature is the presence of smudge or basket cells
(two arrowheads) which are essentially neoplastic cells that got
smudged during slide preparation because of the fragile nature of
these cells. Compare the cell size of CLL cells with a single large
granular lymphocyte (curved arrow).

[CHRONIC LYMPHOCYTIC LEUKEMIA, BLOOD]. This smear shows the

presence of four small neoplastic lymphocytes and three smudge
cells (arrowheads). The diagnosis on blood smear is suspected based
on characteristic morphology and confirmed using flow cytometric
analysis of blood and/or bone marrow which usually shows a
characteristic immunophenotype. The neoplastic cells generally
show expression of CD19, dim CD20, monoclonal immunoglobulin
kappa or lambda light chain, and co-expression of CD5 and CD23.
The cells do not express CD10 or bcl-6. The dim expression of CD20
and surface immunoglobulins is very common.

[CHRONIC LYMPHOCYTIC LEUKEMIA, BLOOD]. Compare the size of

this neoplastic lymphocyte with red blood cells. A CLL cell is only
slightly larger than a red blood cell and shows clumped chromatin,
sometimes likened to a soccer ball. However, atypical CLL cells
may not show this chromatin clumping and diagnosis can only be
made using immunophenotyping.

[CHRONIC LYMPHOCYTIC LEUKEMIA, BLOOD]. Atypical morphology

may manifest by irregular nuclei showing clefts and deep grooves
similar to cells of follicle center cell lymphoma and mantle cell
leukemia. The CLL cells with nuclear clefts, indentations, and deep
grooves are termed Rieder cells. Diagnosis must be established
using immunophenotyping showing expression of CD20, CD19, CD5,
CD23 but no expression of CD10 and cyclin-D1.

[CHRONIC LYMPHOCYTIC LEUKEMIA, BLOOD]. Note three Rieder

CLL cells with nuclear indentations and notches. These cells are
larger than typical CLL cells. About 80% of all CLL cases show
detectable chromosomal abnormalities most commonly deletion of
13q14.3 and less commonly trisomy 12, and deletions of 11q22-23,
17p13, and 6q21 regions. About 40-50% of cases show an
unmutated IgH variable gene whereas the rest show somatic
hypermutations.

Histologic patterns of trephine biopsies from bone marrow reveal patterns that
can be useful in assessing patient risk.
Nodular patterns are made up of mature lymphocytes. The nodules are
larger-than-normal lymphoid follicles and lack clear centers. There is no
interstitial infiltration. Fat cells are preserved. Nodular patterns are
associated with low-risk disease.
Interstitial patterns show some degree of replacement of normal
hematopoietic tissue by mature lymphocytes, but fat cells and bone
marrow structure are preserved. Interstitial patterns are also associated
with low-risk disease.
Diffuse patterns show diffuse lymphoid infiltration with massive
replacement of normal hematopoietic tissue as well as replacement of
fat cells. Diffuse patterns are associated with high-risk disease.

Until recently, B-CLL cells were differentiated from other B-cell

lymphoproliferative diseases by immunophenotyping with 5 cell membrane
protein markers: SmIg (Surface Membrane-bound Immunoglobulin), CD5 (T1
antigen), CD23 (The Fc Receptor for IgE), FMC7 (a specific conformation of
CD20, possibly multimeric and possibly associated with membrane
cholesterol), and CD22 (gp135; a B-cell adhesion molecule).
CD79b (a signal transduction molecule that associates with SmIg) is now
preferred to CD22,
a change that has significantly increased the ability to discriminate between BCLL and other
B-cell disorders.
An immunophenotyping scoring system was developed that gives a value of 1
or 0 according

Because of the limitations of the Rai and Binet systems in predicting the progression of
CLL, other prognostic criteria are being considered; for instance, advanced disease
stage, male gender, CD38 expression >30%, and atypical morphology predict relatively
poor outcomes in CLL. Additionally, karyotyping and molecular biology techniques reveal
that the behavior of certain genetic markers in CLL may offer insights into the molecular
mechanism of the disease and predict treatment outcome.
In a study of 205 patients with CLL, 69% were found to have an abnormal karyotype.
Genetic abnormalities included:
structural abnormality of chromosome 13q14
trisomy 12

Patients with a low level of CD38 expression tend to have a more

favorable clinical course than those with a high level.
In a study where the positivity status for CD38 was set at 30% of
examined cells staining for CD38, median survival among those with
CD38 expression <30% was 288 months (24 years), compared
with approximately 163 months (13.5 years) for those with CD38
expression >30%.
Some investigators have suggested using CD38 expression as a
correlate for the VH gene status. However, in about a third of
patients, the CD38 level does not predict the VH mutation status.

Lymphocyte doubling time (LDT) is clearly related to prognosis in patients with

CLL.
In a study of 100 untreated patients, LDT correlated partially with clinical stage
and with bone marrow patterns, but it also had a clear prognostic significance
by itself.
Patients with an LDT 12 months were likely to have a poor prognosis,
whereas those with an LDT >12 months had a good prognosis, with a
long treatment-free period and survival.

Dhner et al evaluated 325 cases of CLL to assess the frequency and clinical
relevance of genomic aberrations.1 Of the 325 patients, 248 had received no prior
treatment, 39 had received 1 chemotherapeutic agent, and 38 had received 2 or
more chemotherapeutic regimens before the cytogenetic analysis was conducted. 1
Of the 325 patients, 268, or 82%, exhibited abnormalities. The primary endpoint for
this study was survival from time of diagnosis. All cases were evaluated by
interphase cytogenetics. On the basis of regression analysis, the investigators
constructed a hierarchical model of 5 genetic categories for evaluation as prognostic
factors: 17p deletion; 11q deletion but not a 17p deletion; 12q trisomy but not a 17p

A complete remission according to NCI criteria requires that bone

marrow contain fewer than 30% CLL lymphocytes; the criteria
recommend that the clinical significance of lymphoid nodules be
assessed prospectively.
The criteria for the confirmation of a complete remission are similar
for both sets of guidelines although the IWCLL allows focal infiltrates
or nodules in bone marrow while the NCI group specifies no
nodules.
The criteria for partial remission according to IWCLL are limited to a
downshift in clinical stage, whereas the NCI group provides more
specific hematologic requirements similar to those specified for a
complete response.

With the purpose to answer the question, if F is alos better in

the elderly pts, we included in our CLL5ptocol pateients,older
than 65. They were randomized to receive F or Clb. Patients in
the F-arm were treated withthe same dose as the younger pts.
Within the Clb-arm pts received clb in a dose of o.4mg/kg
bodyweight on day 1 and 15. The dose was planned to be
increased up to o.8 mg/kg BW if tolerable

Moreover, in tendency F
treated pts had a shorter
survival time which was 46
months in comparison to 64
months in the Clb arm, but
these18 months difference

Looking for a reason for this

fact, causes of death of both
arms were evaluated: in both
arms most death were CLLrelated, but 4 treatmentassociated deaths occurred in

European Phase III Intergroup CLL Study: p rogression-free

survival

The median observation time was 35 months (range 168) at the

time of this analysis. The median progression-free survival was
significantly longer in the bendamustine group (21.6 months)
compared with the chlorambucil group (8.3 months) (p< 0.0001).
Reference:
Knauf W et al. J Clin Oncol 2009; published online August 3.

Summary
Patients with CLL are mostly elderly, with more than one comorbidity,1,2 and a large proportion of patients will therefore not be
suitable for intensive chemotherapy. Studies with bendamustine as
first-line therapy for CLL show that it provides significantly greater
efficacy than chlorambucil, with a manageable toxicity profile. 3 It
may, in the future, be a possible treatment option for elderly
patients and those who are not suitable for treatment with
chemotherapy. However, bendamustine is currently only indicated
for first-line treatment of chronic lymphocytic leukemia (Binet stage
B or C) in patients for whom fludarabine combination chemotherapy
is not appropriate.

BR, bendamustine/rituximab; CIRS, Cumulative Illness Rating Scale; CLL,

chronic lymphocytic leukemia; CR, complete response; CRi, CR with
incomplete blood count recovery; FCR,
fludarabine/cyclophosphamide/rituximab; IV, intravenously; OS, overall
survival; PFS, progression-free survival; PR, partial response.

BR, bendamustine/rituximab; CLL, chronic lymphocytic leukemia; FCR,

fludarabine/cyclophosphamide/rituximab.

Veronica: This should be the same blue as on other slidesappears to be

more aqua. The client would prefer three dimensional bevel should be
removed. Note font colors, sizes and styles throughout.

Veronica: Lose bevel throughout

AE, adverse event; BID, twice daily; CLL, chronic lymphocytic leukemia; IGHV,
immunoglobulin heavy chain variable region; IRC, Independent Review
Committee; LNR, lymph node ratio; ORR, overall response rate; OS, overall
survival; PFS, progression-free survival.

CLL, chronic lymphocytic leukemia; ECOG PS, Eastern Cooperative Oncology

Group performance score; IWCLL, International Workshop of CLL; SLL, small
lymphocytic leukemia.

CR, complete response; MRD, minimal residual disease; NR, not reported;
ORR, overall response rate; PR, partial response.

La lenalidomide possiede svariati mecchanismi dazione. Leffetto di questa

molecole sembra essere diverso a seconda della patologia.
Il meccanismo e stato descritto nei particolari per quello che riguarda l
inibiozione dei progenitori ertroidi nella del 5 MDS Numeri studi sono stati
condotti nel MM e in una riview dei fratelli Mitsiades vengono descritti
modificazione nel microenviroment, aumento dell apoptosis ecambiamenti nelle
molecole di adesione.
Nella LLC la ricerca e piu indietro ed I meccanismi dazione non sono
conosciuti.
Personalmente io favorisco il meccanismo di immunostimolazione, attraverso il
miglioramento delle sinapsi immunologiche e la stimolazione di T cell e NK cell.
Altri effetti non possono pero essere esclusi.
i The exact mechanism of action is not known, but is likely to be different from
classic chemotherapeutic agents. It also appear to be different in different
disease. In del 5q MDS there is a direct effect on erythroid progenitors as
shown by Pellagatti and coll. In MM the group in Boston as reviewed by
Mitsides point to the relevance of changes to the microenviroment, in adhesion

Dopo vari tentativi (4 anni) siamo riusciti a condurre uno studio di

fase II con lenalidomide in pazienti con malattia in ricaduta o
refrattaria alla fludarabina. Abbiamo deciso di ammistrare il
farmaco in maniera continuata (come era stato fatto nella MDS)
perche volevamo ottenere un inibizione costante del TNF e del
VEGF. La dose iniziale era di 10 mg e si poteva aumentare
gradatament fino a 25 mg al giorno.
We therefore explored the activity of lenalidomide in patients that
had received prior treatment. All patients had been treated with
purine analogue-based combination. Standard inclusion criteria
were used in this study, pat with any neutrophil or PLT count were
eligible. The starting dose was 10 mg. Modeled on the regimen

In questa tabella vengono riassunte le caratteristiche dei pazienti. Si

trattava di un gruppo intensamente pretrattato. I pazienti avevano
svariati fattori prognostici sfavorevoli: b2m elevata, linfoadenopatie
bulky, VH unmutated a 11q e 17p deletions.
The patients characteristics are illustrated in this table. The median
number of prior treatment was five and two patients had received ten or
more lines of therapy. The advanced nature of this population is
reflected by the high median b2M value and the high number of
patients with poor prognostic features. 66% of the cases had
unmutated Vh and 59% of the patients carried a poor prognostic
genomic abnormality. 27% were refractory to fludarabine

I risultati sono stati pubblicati lanno scorso. Risposte obbiettive sono

state ottenute nel 32% dei pazienti. Abbiamo imparato durante questo
studio che le risposte richiedo svariati mesi di trattamento e che
possono migliorare in qualita se la terapia viene continuata. Abbiamo
anche imparato che e molto difficile valutare le risposte quando si usa
un farmaco che viene dato tutti I giorni e non una classica
combinazione di chemoimmunoterapia in cui la risposta migliore viene
determinata quando I 6 cicli sono stati amministrati.
The responses are summarized here. 14 patients achieved a response
according to NCI-WG criteria for an OR rate of 32%. Two patients
achieved a CR, one a nodular PR and ten a PR. Minimal residual
disease was detectable by flow cytometry at a level of 0,01% in one of
the CR and was not dectable by flow and only revealed as low positivity

Queste sono le conclusioni derivate dai due studi di fase II

pubblicati fino ad ora. Attualmete la maggior parte degli studi
nella LLC utilizza trattamento continuo e dosi bassi inizialmente.
In our experience low-dose, continuous lenalidomide shows
activity as salvage treatment in CLL. As anticipated
myelosuppression is common.
Our impression is that the management is different than with
chemoimmunotherapy, patients require a prolonged treatment to
reach their response, as long as 9-12 months
Similarly we believe that the most active dose and schedule in
CLL need to be yet define and clear responses are seen at doses