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

or higher. It is, however, important to understand that
these regimens have not been prospectively studied in
young adults; rather they have been adopted. Pediatric
regimens are generally more intensive, include far more
aspariginase, and reflect a greater protocol discipline,
especially about timeliness. 73
Philadelphia chromosome-positive
Until recently, Philadelphia chromosome-positive
ALL (Ph+) was considered the ALL with the poorest
prognosis. With chemotherapy alone, most patients did
not survive one year. 74–79 Allogeneic transplant improved
the survival significantly 78,80–84 and became the gold standard
for treatment. The advent of tyrosine kinase
inhibitors (TKIs) has completely revolutionized the
treatment of Ph+ ALL and has become a part of a new
gold standard.
The most important issues regarding the treatment of
Ph+ ALL in the TKI are:
Induction
• How to combine TKI with chemotherapy?
• Which TKI to choose?
• TKI and CNS
Postinduction
• In the TKI era, is allotransplant still a must?
Maintenance
• TKI after transplant?
Induction. The combination of conventional chemo -
therapy and imatinib mesylate has improved the CR
rate and the OS compared to historical controls
[reviewed in ref. #85)]. The optimal dose of imatinib is
London, United Kingdom, June 9-12, 2011
Figure 3. The MRC/ECOG
international ALL Trial.
Reproduced from Goldstone et
al. Blood, 2008; with permission.
(A) Overall survival from
diagnosis of all patients aged
16–64, including Ph-positive
patients. (B) Among Ph-negative
patients, there was a significant
advantage in the overall
survival for patients with a
donor compared with those
without a donor. (C) Significant
survival advantage of Ph-negative
patients at standard risk,
defined as aged less than 35
years, with a low white cell
count at presentation and
responding within phase I of
induction. (D) Lack of significant
benefit for Ph-negative
patients at high risk. The
reduced benefit for patients
with a donor is due almost
entirely to excess of transplantrelated
mortality among
patients over age 35 years. (E)
Overall survival among
patients randomized to receive
autologous transplant versus
standard consolidation/maintenance
chemotherapy.
not known, as studies have used different doses
between 400–800 mg without direct comparisons. The
GMALL phase 2 multicentric prospective trial 86 studied
the best way to combine chemotherapy and imatinib –
concurrent versus alternative administration. The coadministration
group resulted in higher rates of PCR negativity
(P=0.01) with somewhat higher toxicity but without
significant improvement in survival. 87 The
MRC/ECOG study emphasized the importance of early
administration of imatinib; not later than phase II of
induction.
For patients who undergo allogeneic transplantation,
it is not clear whether aggressive chemotherapy is needed
for induction. The primary data from the GRAAPH-
2005 study 88 reported comparable results of two groups,
which received either aggressive induction (Hyper-
CVAD) or non-aggressive one (vincristine and dexamethasone)
combined with imatinib prior to allogeneic
transplant.
Most of the studies included imatinib as the first
known TKI. Dasatinib, a second generation TKI with a
broader spectrum of tyrosine of kinase inhibition, has
the potential to be more effective than imatinib but this
has only recently been evaluated as first-line therapy. A
recent study confirmed the safety and efficacy of dasatinib
as first line therapy when given with steroids
only. 89 In another European study, 90 dasatinib was given
together with low intensity chemotherapy as first line
therapy for 71 elderly patients. The CR rate was 90%
and the relapse free survival was 22.1 months. Another
advantage of dasatinib is its good penetration to the
CNS compared with imatinib. 91 Currently, there is no
Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) | 15 |