This document provides guidelines for the management of relapsed acute lymphoblastic leukemia in childhood. It discusses that while treatment advances have improved survival rates for initial childhood ALL to over 80%, approximately 20% of patients will experience relapse. The prognosis and treatment approach for relapsed ALL depends on factors like the time since initial diagnosis and site of relapse. Treatment aims to induce a second remission through chemotherapy, followed by either continued chemotherapy or allogeneic stem cell transplantation depending on the risk group. High-risk patients benefit most from transplantation while stem cell transplantation remains controversial for intermediate-risk patients. The challenges in relapsed ALL management in limited resource settings are also addressed.

1. Guidelines for the management of relapsed acute lymphoblastic
leukemia in childhood

2. Apollo Medicine 2011 December
Review Article
Volume 8, Number 4; pp. 297–301
© 2011, Indraprastha Medical Corporation Ltd
Guidelines for the management of relapsed acute lymphoblastic
leukemia in childhood
Amita Mahajan*
*Senior Consultant, Paediatric Hematology and Oncology, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi – 110076, India.
ABSTRACT
Considerable progress has been made in the treatment of newly diagnosed childhood acute lymphoblastic leuke-
mia. With the use of intensive, risk-stratified multiagent chemotherapeutic protocols, over 80% of patients can hope
to be long-term survivors. However, despite optimal treatment, about 20% of patients relapse. The treatment of
these children poses a major challenge. The prognosis of these patients depends on a number of factors including
time since diagnosis, the site of relapse and immunophenotype. The choice of postinduction therapy depends
on these prognostic factors. Considerable work has been done to identify the subgroups of relapsed patients whose
outcomes are significantly altered by allogeneic bone marrow transplant. In our scenario, the limited availability of
allogeneic bone marrow transplant due to a host of factors renders the management of these children even more
challenging.
Keywords: Acute lymphoblastic leukemia, relapse bone marrow transplant
Correspondence: Dr. Amita Mahajan, E-mail: mahajanamita1@gmail.com
doi: 10.1016/S0976-0016(11)60011-2
Considerable advances have been made in the treatment of
childhood acute lymphoblastic leukemia (ALL) over the past
few decades with long-term cure rates approaching 85% in
optimally treated children. However, despite optimal therapy,
about 15–20% children will sustain a relapse. The treatment
of children with relapsed ALL continues to be challenging.
In the 1980s, relapsed ALL was regarded an incurable
disease. However, with sustained efforts and current sal-
vage protocols, about 70–85% can hope to achieve a second
remission, but only about 40% of these can hope to achieve
a long-term cure. The optimal approach after achieving
remission depends on a number of prognostic factors.
The prognosis for a child with ALL whose disease
recurs depends on the time from diagnosis, the site of
relapse, and immunophenotype.1,2
Patients with precursor
B-cell ALL who experience either an isolated marrow
relapse while on treatment or within 6 months of comple-
tion of therapy or a combined relapse within 18 months of
diagnosis have a very poor prognosis. Patients with an
extramedullary relapse while on treatment or within 6
months of completion of therapy, patients with precursor
B-cell ALL and a marrow relapse with or without an
extramedullary relapse >6 months after completing therapy,
and patients with precursor B-cell ALL and a combined
marrow relapse between 18 and 36 months from the diag-
nosis have an intermediate prognosis. Patients with a late
extramedullary relapse (occurring more than 6 months after
completing therapy) have a good prognosis. Patients with
T-cell ALL who experience a bone marrow relapse with
or without a concurrent extramedullary relapse at any
point during treatment or posttreatment have a very poor
prognosis.3,4
Despite these findings, no evidence exists that the early
detection of relapse by frequent surveillance (complete
blood counts or bone marrow tests) improves the outcome.5
The German Berlin–Frankfurt–Munster (BFM) group
has developed risk stratification for relapsed ALL.6
In this
risk stratification, the duration of the first complete remis-
sion and the immunophenotype are associated with the
outcome (Tables 1 and 2).
MANAGEMENT OF RELAPSED CHILDHOOD
ACUTE LYMPHOBLASTIC LEUKEMIA
The selection of therapy for the child whose disease recurs on
or shortly after therapy depends on many factors including

3. 298 Apollo Medicine 2011 December; Vol. 8, No. 4 Mahajan
© 2011, Indraprastha Medical Corporation Ltd
prior treatment, whether the recurrence is medullary or
extramedullary, and individual patient considerations.
The core principle in the management of relapsed
ALL is to achieve a second remission followed by either
(i) continuing chemotherapy or (ii) allogeneic hematopoietic
stem cell transplantation.
REINDUCTION CHEMOTHERAPY
A lot of work has been done to design the optimal salvage
protocols. These protocols need to combine drugs that are
likely to be effective in previously treated patients and at the
same time limit treatment-related morbidity and mortality
in these patients which is significantly higher than the treat-
ment naive group.
There are many salvage protocols. The two most com-
monly used are from the UK-ALL group6
and the BFM
group.7
All salvage protocols essentially aim at achieving a
second remission using drugs identical to those used in the
initial induction phase: Dexamethasone, epirubicin, vincris-
tine and L-asparaginase.
Other drug combinations used for inducing remission
for refractory relapsed ALL are the FLAG (fludarabine and
cytarabine)8
and FLAG-Ida (fludarabine, idarubicin, and
cytarabine). Newer agents such as clofarabine have gener-
ally been tried in subsequent or posttransplant relapses.9
Relapsed T-cell ALL is notoriously difficult. Treatment of
children with relapsed T-cell ALL with the T-cell selective
agent nelarabine has demonstrated an approximately 50%
response rate.10
The UK-ALL induction block comprises dexamethasone,
epirubicin, vincristine and L-asparaginase followed by a
consolidation block with systemic methotrexate, etoposide,
cytarabine, vincristine, dexamethasone, epirubicin, cyclo-
phosphamide, and 6-thioguanine.7
This is then followed by
continuation blocks again using 6-MP and methotrexate
and the pulses of prednisolone and vincristine but also
cytarabine, etoposide, and cyclophosphamide.
The conceptual backbone of BFM relapsed ALL proto-
cols6
is a series of short, intensive multiagent chemotherapy
courses including the most known drugs with anti-leukemic
efficacy with a 2-week interval between blocks to allow
adequate marrow recovery. The BFM protocol comprises
alternating blocks of chemotherapy after a cytoreductive
phase followed by conventional maintenance therapy with
daily 6-TG and biweekly methotrexate. The alternating
blocks R1 (prednisolone, 6-MP, vincristine, vindesine,
methotrexate, cytarabine, teniposide, and L-asparaginase)
and R2 (dexamethasone, vindesine, methotrexate, ifosfa-
mide, and daunorubicin). All patients receive intrathecal
chemotherapy. The block therapy concept is feasible, effec-
tive, and relatively well tolerated. Thus, it is incorporated
into many other treatment protocols for relapsed ALL.11,12
TREATMENT AFTER REMISSION
A number of trials have looked at hematopoietic stem cell
transplantation (HSCT) versus continuing chemotherapy for
these patients.13–16
The choice of further therapy is deter-
mined by the predicted risk of subsequent relapse as well as
Table 1 The German Berlin–Frankfurt–Munster relapse risk group assignment for precursor B-cell acute lymphoblastic leukemia.
Extramedullary relapse Combined bone marrow Marrow relapse
and extramedullary relapse
Very early relapse (<18 months from diagnosis) Intermediate High High
Early relapse (>18 months from diagnosis and Intermediate Intermediate High
<6 months from completion of therapy)
Late relapse (>6 months from completion of therapy) Standard Intermediate Intermediate
Table 2 The German Berlin–Frankfurt–Munster relapse risk group assignment for T-cell acute lymphoblastic leukemia.
Extramedullary relapse Combined bone marrow Marrow relapse
and extramedullary relapse
Very early relapse (<18 months from diagnosis) Intermediate High High
Early relapse (>18 months from diagnosis and Intermediate High High
<6 months from completion of therapy)
Late relapse (>6 months from completion of therapy) Standard High High

4. Guidelines for the management of relapsed ALL in childhood Review Article 299
© 2011, Indraprastha Medical Corporation Ltd
the quantum of benefit expected from HSCT which is asso-
ciated with significantly higher morbidity and mortality. In
countries like ours, this is further determined by the feasi-
bility of offering HSCT in view of the lack of a donor regis-
try, limitations of access and the funding for HSCT.
There is adequate evidence now to suggest that mini-
mal residual disease status after the induction of second
remission is of prognostic significance and may further
define the choice of postinduction therapy.17,18
The suggested treatment strategy is outlined based on
their risk as determined by the BFM criteria.
LOW-RISK RELAPSED ACUTE
LYMPHOBLASTIC LEUKEMIA
For patients with a late marrow relapse, a primary chemo-
therapy approach should be considered with HSCT reserved
for a subsequent marrow relapse.18
Whether transplantation
benefits patients with late marrow relapse but with a high
level of residual disease after reinduction treatment is cur-
rently under evaluation.
INTERMEDIATE-RISK RELAPSED ACUTE
LYMPHOBLASTIC LEUKEMIA
For these patients, the benefit of HSCT versus continuing
chemotherapy remains unclear as some of the advantages
are offset by the increased treatment-related mortality for
children who undergo HSCT. A Children’s Cancer Group
trial (CCG-1941) comparing chemotherapy versus HSCT
(either matched sibling or matched unrelated donor) was
not able to show a significant advantage for HSCT over
chemotherapy for patients relapsing <12 months after stop-
ping therapy.16
HIGH-RISK RELAPSED ACUTE
LYMPHOBLASTIC LEUKEMIA
Hematopoietic stem cell transplantation should be strongly
considered for patients withT-cellALL and marrow relapse;
or patients with precursor B-cell ALL and marrow relapse
occurring while on treatment or within 6 months of termi-
nation of therapy; or late marrow relapse with high tumor
load as indicated by a peripheral blast count of 10,000/μL
or more. For such patients, allogeneic transplant from an
HLA-identical sibling or matched unrelated donor which is
performed in the second remission has been reported to
result in longer leukemia-free survival when compared with
a chemotherapy approach.
Despite transplant, however, the outcome of this sub-
group is very poor especially if relapsing on therapy.
MATCHED UNRELATEDTRANSPLANTATION
The outcome following matched unrelated donor trans-
plants has improved significantly over the past decade
and may offer an outcome similar to that obtained with the
matched sibling donor transplants.19,20
Treatment-related
mortality remains high (>20%), and the rates of clinically
extensive chronic graft-versus-host disease remain high.
However, there is some evidence that the matched unre-
lated donor transplantation may yield a lower relapse
rate.21
There is also evidence that transplant conditioning
regimens that include total-body irradiation produce
higher cure rates than chemotherapy-only preparative
regimens.22
A Center for International Blood and Marrow Trans-
plant Research study suggests that the outcome after one
or two antigen mismatched cord blood transplant may be
equivalent to that for a matched family donor or for a
matched unrelated donor.23
In certain cases, where no suit-
able donor is found or an immediate transplant is considered
crucial, a haploidentical transplant utilizing large doses of
stem cells may be considered. For all types of transplants,
pre-transplant level of minimal residual disease (MRD) is
an important prognostic factor; patients with high levels of
pre-transplant MRD have a very poor prognosis.24
SECOND RELAPSE
For patients relapsing after an allogeneic HSCT for relapsed
ALL, a second ablative allogeneic HSCT may be feasible.
However, many patients will be unable to undergo a second
HSCT procedure due to failure to achieve remission, early
toxic death or severe organ toxicity related to salvage
chemotherapy. Among the highly selected group of patients
who are able to undergo a second ablative allogeneic
HSCT, about 10–30% may achieve long-term event-free
survival (EFS). Prognosis is more favorable for patients
with longer duration of remission after the first HSCT and
for patients with complete remission at the time of the
second HSCT.

5. 300 Apollo Medicine 2011 December; Vol. 8, No. 4 Mahajan
© 2011, Indraprastha Medical Corporation Ltd
ISOLATED CENTRAL NERVOUS SYSTEM
RELAPSE
With the improved success of treatment of children with
ALL, the incidence of isolated extramedullary relapse has
decreased. The incidence of isolated central nervous system
(CNS) relapse is <10% and testicular relapse is <5%.
While the prognosis for children with isolated CNS relapse
had been quite poor in the past, aggressive systemic
and intrathecal therapy followed by craniospinal radiation
has improved the outlook particularly for patients who did
not receive cranial radiation during their first remission.25
In a Paediatric Oncology Group (POG) study using this
strategy, children who had not previously received radiation
therapy and whose initial remission was 18 months or
greater had a 4-year EFS rate of about 80% compared with
EFS rates of about 45% for children with CNS relapse
within 18 months of diagnosis.26
In a follow-up study, chil-
dren who had not previously received radiation therapy and
with initial remission of 18 months or more were treated
with intensive systemic and intrathecal chemotherapy for
1 year followed by 18 Gy of cranial radiation only. The
4-year EFS was 78%. Children with an initial remission
of <18 months also received the same chemotherapy
but had craniospinal radiation (24 Gy cranial/15 Gy
spinal) as in the first POG study. This group’s 4-year EFS
was 52%.
A number of case series describing stem cell transplan-
tation in the treatment of isolated CNS relapse have
been published. This approach may be of value in patients
with high risk of relapse using chemoradiation treatment.
In a study comparing the outcome of patients treated with
either HLA-matched sibling transplants or chemoradiother-
apy as in the POG studies above, however, 8-year prob-
abilities of leukemia-free survival adjusted for age and
duration of first remission were similar (58% and 66%,
respectively).27
ISOLATEDTESTICULAR RELAPSE
The standard approach for treating isolated testicular
relapse is to administer chemotherapy plus radiation ther-
apy. While there is limited clinical data concerning the out-
come without the use of radiation therapy, this treatment
strategy is being tested in clinical trials. The results of the
treatment of isolated testicular relapse depend on the timing
of the relapse. The 3-year EFS of boys with overt testicular
relapse during therapy is about 40%; it is about 85% for
boys with late testicular relapse.
TREATMENT OPTIONS UNDER CLINICAL
EVALUATION
A novel nucleoside analog clofarabine has been tried in
children with relapsed ALL as well as acute myeloid leuke-
mia (AML) and appears promising.28
It is well tolerated
and shows significant antileukemic activity in heavily pre-
treated children including those relapsing post-bone mar-
row transplantation.
A number of clinical trials are currently underway to
investigate novel treatment approaches.29,30
These include
the evaluation of new formulations of existing chemothera-
peutic agents, new anti-metabolites and nucleoside analogs,
monoclonal antibodies against leukemia-associated anti-
gens and molecular therapies that target the genetic abnor-
malities of the leukemia cells and their affected signaling
pathways.
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