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
When a patient has CNS involvement at diagnosis,
most protocols attempt to eradicate the blasts from the
CNS by more intensive (bi-weekly) IT therapy, usually
in combination with radiotherapy, and then continue to
follow the regular protocol.
Post-remission therapy
Consolidation/maintenance. Most remission therapy for
young adults with ALL remains the most challenging
and controversial aspect in the management of ALL.
Suffice it to say that there are virtually no long-term survivors
if no post-remission therapy is given. An overall
suggested schema for the management of ALL is outlined
in Figure 2, emphasizing the complexities in postremission
management. Historically, patients were
offered treatment based on pediatric regimens of ALL
on the assumption that this therapy would lead to
results in adults comparable with those in children. 61,62
For those patients in whom an allogeneic transplant is
not an appropriate option, standard post remission therapy
consists of consolidation therapy followed by maintenance
therapy for a total of 2.5 years. Consolidation
therapy includes high dose methotrexate intercalating
with regimens that include asparaginase and cyclophosphomide.
Maintenance therapy for 2 years after induction and
consolidation remains a standard of care for patients not
transplanted. Randomized studies, mostly in pediactric
ALL, have mitigated against any attempts in adults to
omit maintenance therapy, as this invariably leads to an
inferior outcome. The backbone of maintenance
remains methotraxate and 6-mercatopurine. It has not
been demonstrated that including cycles of high dose
therapy in the midst of the prolonged maintenance is
beneficial. 63
Allogeneic transplantation. Allogeneic transplantation
offers the most potent post remission anti-leukemic
therapy. This is achieved through the graft versus
leukemia (GvL) effect, which is particularly potent in
first remission. 64
Over the past two decades, several studies of allogeneic
transplantation in first remission were conducted
and there was general agreement that this was a recommended
modality for particularly high risk patients,
such as those with the Philadelphia chromosome.
Gradually, the concept of high risk was broadened to
include some other unfavorable cytogenetics on those
who did not respond rapidly in induction. Using such
criteria, several studies reported a distinct advantage for
high risk patients who had a human leukocyte antigen
(HLA)-compatible donor. 3,54,65 A meta-analysis of seven
studies of transplants in ALL also reported significant
advantages for sibling allogeneic transplantation in high
risk ALL patients compared with other therapeutic
mordalities. 66 None of these studies found any benefit
for allogeneic transplants for patients who were not at
high risk.
The International ALL trial, conducted by the MRC in
the United Kingdom and ECOG in the US, was the
largest prospective study of transplantation in ALL with
the aim of defining the role of allogeneic transplant,
autologous transplant, and chemotherapy for adult
patients in first CR up to age 60 years. The hallmark for
this study was that all patients received the identical
therapy, irrespective of their risk assignment, a concept
that was a deviation from the thrust of most clinical trials
of therapy in ALL, which are so called “risk-adapted”.
The trial recruited of 2000 patients over 13 years
and the results are shown in Figure 3. The survival of all
patients from diagnosis was 39%, with a significantly
improved overall survival for patients who had a sibling
donor (53% versus 45% at 5 years p=0.01). Despite the
significantly reduced relapse rate among all patients
with a donor, the high non-relapse mortality (NRM) for
high risk patients abrogated the reduction in relapse,
such that a definitive advantage could not be demonstrated
among high risk patients (Figure 3D). In contrast,
among the 239 patients with standard risk who had a
donor, the overall survival was significally improved
over the 323 patients without a donor (62% versus
52%, p=0.02) (Figure 3C).
Reduced-intensity Conditioning. Reduced-intensity conditioning
(RIC) for ALL is clearly an attractive option for
older patients or those with comorbidities. In the international
ALL trial, high risk patients had an excessively
high NRM of 36% at 2 years, which was almost entirely
driven by assigning patients over the age of 35 to the
high risk group. For such patients, RIC would be an
attractive option. Data have been published indicating
that RIC transplants are feasible both in first and second
remission ALL, with results that are not significantly
worse than using a full intensity transplant. Such data
have been reported from the Center for International
Blood and Marrow Transplant Research (CIBMTR) 67
and the European Bone Marrow Transplant registry
(EBMTR). 68 In the later, the relapse rate was greater for
patients undergoing RIC compared with myeloblative
transplants but the NRM, as expected, was lower. RIC
is currently being prospectively evaluated by the NCRI
in Britain but caution needs to be advised in using RIC
transplants for fit younger individuals with ALL. 69
Autologous transplantation. There have been several
studies of autologous transplants comparing this with
standard therapy. None of the studies showed a significant
benefit for autologous transplants over chemotherapy
although the study conditions of all these trials are
different. 54,65,70,71 The large MRC/ECOG study prospectively
randomized all patients who did not have a sibling
donor to an autologous transplant versus consolidation
maintenance therapy for 2.5 years. Although the
mortality from autologous transplant was not greater,
the overall survival was significally superior in the
chemotherapy arm due to the lower relapse rate among
patients who received ongoing consolidation maintenance
therapy (Figure 3E). Whether additional post
autograft therapy may alter these results is unknown,
but it is currently difficult to recommend autologous
transplant for any patient with ALL, recognizing that
the potential benefit among individual subgroups are
not necessarily negated by these findings.
Adolescents and young adults with ALL. Multiple reports
have described the results of adolescents and, in some
cases, young adults, treated on pediatric regimens and
have retrospectively compared this with historical data
of patients in similar age groups treated on adult protocols
[reviewed in ref. #72)]. As a result of these data,
many groups have now incorporated a pediatric regimen,
and this is being used even in adults up to age 29
| 14 | Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1)