H e m a t o lo g y E d u c a t io n - European Hematology Association

16 th Congress of the European Hematology Association
CLL B-cells. 14 Dasatinib also induces apoptosis of CLL Bcells
in vitro, with cells that have unmutated IgVH genes
appearing more sensitive, and this agent is also able to
overcome CD40-mediated drug resistance, and to sensitize
the tumor cells to chlorambucil and fludarabine in
vitro. 15 A phase II study of dasatinib in mostly high risk
patients with relapsed or refractory CLL, showed partial
responses in 20%, although in two-thirds of cases. there
was also significant myelosuppression. 16
The importance of Syk in BCR-signaling has made it
an attractive target for the development of novel therapies
in CLL. Syk is constitutively activated in CLL Bcells,
and its inhibition results in a reduction of BCRinduced
Akt activation and Mcl-1 upregulation. 17 The
Syk inhibitor fostamatinib was demonstrated to
decrease BCR-signaling, selectively reduce tumor cell
proliferation, and prolong animal survival mice in the
Eμ-TCL1 transgenic mouse model. 18 A phase I/II study
of fostamatinib in a variety of B-cell lymphoproliferative
disorders, showed the highest response rate in CLL,
with 55% of patients achieving partial remission (PR).
IgVH mutation analysis was not reported in this study,
although clinical responses were observed in patients
with and without ZAP-70 expression. 19 Similarly, there
has been interest in developing inhibitors of Btk as a
therapeutic tool in CLL. Treatment of primary CLL Bcells
with the Btk inhibitor PCI-32765 results in significant
apoptosis that is caspase dependent. There was no
correlation between response to PCI-32765 and prognostic
factors, such as IgVH gene mutation status, suggesting
potential efficacy in high risk patients. This
agent also appears to have effects on the microenvironment,
by blocking the protective effect of factors, such
as CD40 ligand (CD40L), tumor necrosis factor-a (TNFa),
IL-6, and B-cell activating factor (BAFF). 20 An ongoing
phase I clinical trial of PCI-32765 in relapsed or refractory
CLL has shown it to be relatively well tolerated, with
overall response rates of 64% in an interim analysis. 21
Inhibitors of PI3K are also under investigation as
potential treatments for CLL. The PI3K pathway has
been shown to play a pivotal role in CLL B-cell growth,
with sustained activation being critical for their survival.
22 Constitutive activation of this pathway in the
malignant cells prevented the downregulation of (B-cell
lymphoma-xL) Bcl-xL and the caspase inhibitor proteins
FLICE-inhibitory protein ligand (FLIPL) and X-linked
inhibitor of apoptosis protein (XIAP). CAL-101 is a
small-molecule inhibitor of the p110δ isoform of PI3K,
which is generally restricted to cells of hematopoietic
origin. It has been demonstrated to promote caspase
dependent apoptosis in primary CLL cells independently
of common prognostic markers. 23 CAL-101 has also
been shown to overcome the anti-apoptotic effects of
CD40L, TNF-a, and fibronectin, and to inhibit the protective
effects of stromal cells. 24 There was also pre-clinical
evidence of an effect on T-cells, with decreased production
of various inflammatory and anti-apoptotic
cytokines by activated T-cells. A phase I study of the use
of single agent CAL-101 in patients with relapsed or
refractory CLL has shown it to be well tolerated, with
partial remissions being observed in 33% of patients.
Interestingly, it was noted to be particularly efficacious
in reducing lymphadenopathy, with over 90% of
patients showing a lymph node response. An increase in
the circulating lymphocytosis in the first two cycles was
observed in the majority (60%) of patients, which, with
the improvement in the lymphadenopathy, suggests a
drug-mediated shift of lymphocytes from the nodes to
the peripheral blood. 25 Early dose finding studies of
CAL-101 in combination with rituximab or bendamustine
look encouraging, and other therapeutic combinations
with drugs, such as the immuno-modulatory
agent, lenalidomide, are of potential interest. 26
Role of stem cell transplantation
A major challenge remains the decision as to which
other patients should be considered for allogeneic SCT
and when in their disease, course choice is usually
reduced intensity conditioning allogeneic SCT is most
frequently used. 27 The European Bone Marrow Transplant
(EBMT) guidelines outline indications for SCT in CLL. 28
In addition to those with p53 abnormalities, allogeneic
SCT is also recommended for younger patients with
CLL who fail to respond to, or relapse within 2 years of
first line chemoimmunotherapy.
Impact of performance status on treatment
Most patients with CLL are elderly, but age alone is not
a contraindication to the use of FCR 29 and the limiting factors
for its use are impaired renal function, poor performance
status, and comorbidities. There was no upper age
limit in the GCLLSG CLL8 trial (FCR versus FC), but
patients had to meet eligibility criteria including creatinine
clearance greater than or equal to 70 cc/minute and
good physical fitness as assessed by a Cumulative Illness
Rating Scale (CIRS) less than or equal to 6. There was no
difference in side effects when comparing patients
younger or older than 70 years old in that trial. Thus, FCR
can certainly be utilized in older, fit patients with CLL. In
the GCLLSG CLL5 trial in older patients, fludarabine
resulted in a significantly higher OR rate and CR rate than
chlorambucil; there was no difference in PFS or OS. 30 The
best treatment for elderly unfit patients or those with
complex comorbidities remains to be determined.
Ongoing clinical trials are assessing the addition of monoclonal
antibodies, including rituximab, ofatumumab, or
GA101 to chlorambucil compared with chlorambucil
alone. Other agents being assessed in clinical trials in this
patient population include bendamustine alone and in
combination with rituximab, lenalidomide, ABT263,
PCI-32765, and CAL-101 alone or with rituximab.
Richter's transformation
Richter’s transformation to high-grade non-Hodgkin’s
lymphoma occurs in approximately 5–10% of patients
with CLL. 31 The large cells of RS either arise through a
transformation of the original CLL clone by the acquisition
of new genetic abnormalities, or, less frequently,
represent a new secondary neoplasm. The clinical outcome
of the disease is generally poor with median survival
of months from transformation, but prognosis is
better when transformation occurs in previously
untreated patients. Treatment is with regimens that are
effective in high-grade NHL and although numerous
regimens have been proposed, there is no consensus on
the best therapeutic approach for RS patients and novel
agents are urgently required.
| 102 | Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1)