Novel agents and biomarkers for acute lymphoid leukemia
Journal of Hematology & Oncology
Novel agents and biomarkers for acute lymphoid leukemia
Yanmin Zhao 0
He Huang 0
Guoqing Wei 0
0 Bone Marrow Transplantation Center, The First Affiliated Hospital of Zhejiang University , No. 79 Qing Chun Rd, Hangzhou 310003 , China
New genetic markers for adult acute lymphoblastic leukemia (ALL) have been found to have prognostic impact, such as the lymphoid transcription factor gene IKZF1 alterations, which are associated with a high rate of leukemic relapse in B-ALL. Although complete remission rates by induction chemotherapy in ALL are now high, the long-term survival is still disappointing. Improvements in the survival outcome of ALL have been observed in young adults as a result of the use of pediatric inspired regimens and the broadening of the number of patients who are eligible for allogeneic SCT. Development of new and less toxic agents also provide promise to improve the outcome in adult ALL, such as tyrosine kinase inhibitors in Ph-positive ALL, rituximab in CD20-positive disease, blinatumomab in precursor B-ALL and nelarabine in T-lineage ALL. Challenges for the future are to implement genomic profiling into the clinical setting to guide risk stratification and providing novel targets for tailored therapies.
Acute lymphoblastic leukemia; Genetic alteration; Philadelphia chromosome; Tyrosine kinase inhibitor; Monoclonal antibodies; Stem cell transplantation
Acute lymphoblastic leukemia (ALL) is a biologically and
clinically heterogeneous neoplasm of lymphoid
progenitors, with approximately 85% of cases being of B-cell
lineage and 15% of T-cell lineage. In contrast to childhood
ALL, in whom approximately 90% are now cured ,
adults with ALL usually carry a worse prognosis with a
long-term survival rate less than 35-40% , even with
allogeneic hematopoietic stem cell transplantation
(alloSCT). The current understanding of the biologic
determinants of treatment failure in ALL is limited, and the
treatment of refractory or relapsed ALL remains a major
challenge. By summarizing recent dvelopments and
particularly the highlights from the 2012 ASH Annual Meeting,
this study will review some latest advances in the biological
features of adult ALL, with an emphasis on the role of
genetic alteration on prognosis of this malignancy and
treatment approaches to both Philadelphia
chromosomepositive (Ph+) and negative (Ph-) ALL.
Integration of genetic markers into risk stratification
The inherent heterogeneity of ALL requires an accurate
assessment of risk to aid treatment decisions. In the past,
the classic prognostic factors were age, presenting white
blood cell (WBC) counts, cytogenetic abnormalities and
upfront response to induction therapy. One of the
strongest adverse prognostic features is the presence of the Ph
chromosome t(9;22). Recently, a retrospective analysis of
the Mayo Clinic leukemia database has identified high risk
cytogenetics [7, del(7p), +8, MLL translocations, t(1;19),
t(17;19), t(5;14)], very high risk cytogenetics categories
[t(4;11), t(8;14), complex ( 5 abnormalities), hypodiploidy,
triploidy] , low platelet counts and poor Performance
Status (PS) at diagnosis were independent predictors of
inferior outcomes in patients with Ph-negative ALL .
Detection of minimal residual disease (MRD) is also used
to identify high-risk patients . These prognostic clinical
features of ALL were summarized here in Table 1.
Nowadays, microarrays and next generation sequencing
provide new approaches to profile ALL genomes. These
studies have identified some new subtypes of ALL
harboring recurring submicroscopic genetic alterations, several
of which have clear implications for risk stratification and
targeted therapeutic intervention.
Table 1 Prognostic clinical features of ALL
Adverse outcome with advancing age
Presenting WBC count Adverse for B-ALL > 30
In response to therapy
Adverse for T-ALL >100
Poor PS at diagnosis were an independent
predictor of inferior outcomes
Adverse: t(9;22), t(4;11), t(8;14), complex
( 5 abnormalities), hypodiploidy, triploidy,
-7, del(7p), +8, MLL translocations, t(1;19),
Time to initial response Adverse: failure to attain complete remission
within 4 weeks of induction
Adverse: detection at various time-specific
points in several studies
Till now, more than 50 recurring genetic alterations have
been identified, and many of the genes involved encode
proteins with key roles in lymphoid development (PAX5,
IKZF1, and EBF1), transcriptional regulation (ETV6, ERG),
lymphoid signaling (BTLA, CD200, TOX, BLNK, VPREB1),
cell-cycle regulation and tumor suppression (CDKN2A/
CDKN2B, RB1, PTEN), and drug responsiveness (the
glucocorticoid receptor NR3C1) . These specific genetic
alterations cooperate in leukemogenesis, however, few
have been found to have definite prognostic impact, with
the notable exception of alterations of the lymphoid
transcription factor gene IKZF1 in B-ALL.
IKZF1 encodes IKAROS, a zinc finger transcription
factor that is required for the development of all
lymphoid lineages . During the last 5 years, IKZF1 has been
identified as one of the most clinically relevant tumor
suppressors in ALL [8,9]. Deletion or sequence mutation
of IKZF1 are detected in more than 70% of BCR-ABL1+
lymphoid leukemia, including de novo ALL and chronic
myeloid leukemia at progression to lymphoid blast crisis,
 and are associated with poor outcome in BCR-ABL1+
adult ALL . Moreover, a subset of BCR-ABL1 negative
B-ALL patients with IKZF1 alterations exhibit a
geneexpression profile similar to BCR-ABL1+ ALL, named
as BCR-ABL1like ALL. These cases may have alternative
genetic events resulting in aberrant activation of tyrosine
kinase signaling pathways similar to those downstream
of BCR-ABL1, including rearrangement of CRLF2 and
activating mutations of Janus kinases (JAK1/2) [12,13].
The prognosis of BCR-ABL1like ALL is poor. In the
COG AALL0232 study of high-risk B-progenitor ALL,
the event-free survival (EFS) for BCR-ABL1like cases
was 62.6% 6.9% compared with 85.8% 2.0% for non
BCR-ABL1like cases (P < 0.0001) and was associated
with poor outcome after adjustment for age, sex, WBC
at presentation, and levels of MRD .
In addition to IKZF1, other genetic alterations were also
identified to have some prognostic impact on ALL and
incorporated into risk stratification algorithms (Table 2).
For example, B-ALL cases with CRLF2 rearrangements,
JAK1/2 mutations , CDKN2A/B deletions , TP53
deletions/mutations , or CREBBP deletions/mutations
 had inferior outcomes in terms of response to
chemotherapy, overall survival, or incidence of relapse. For adult
T-ALL, NOTCH1 and/or FBXW7 (N/F) mutations were
associated with a favorable outcome [18,19], while
N/KRAS mutations or PTEN deletions/mutations
demonstrated trends to a worse outcome [20,21]. Therefore,
Trinquand A et al. propose a new T-ALL oncogenetic
classifier defining low-risk patients as those with N/F
mutation but no RAS/PTEN mutation, allowing
identification of nearly 50% very good prognosis T-ALL adults
. Recently, mutations in the cytosolic 5-nucleotidase
II gene (NT5C2), were identified to drive resistance to
treatment with nucleoside analog therapies in T cell or
B-precursor ALL .
Current treatment options for treatment of Ph-positive
acute lymphoblastic leukemia
Philadelphia chromosome/BCR-ABLpositive ALL has
long been recognized as a high-risk subset of adult ALL
with the most unfavorable prognosis. Published data show
a disappointing long-term survival of 20% or less with
chemotherapy alone . Introduction of the tyrosine
kinase inhibitors (TKIs), most commonly imatinib (IM)
in combination chemotherapy has led to an encouraging
treatment outcome, [24-28] with complete remission rates
exceeding 90% and estimated overall survival (OS) ranging
from 30% to 70%. The proportion of patients able to
proceed to and benefit from allo-SCT in CR1 has
increased with TKI-based therapy, and there is no evidence
that IM has an adverse effect on transplant-related
morbidity or mortality. Nevertheless, there are still many
challenges related to this disease, including the selection
of appropriate pre-transplant therapy, the correct use
of TKIs after transplant, and development of potential
therapeutic strategies to overcome disease resistance.
Furthermore, the incidence of Ph + ALL increases with
age, and a significant proportion of elderly patients are
not eligible for SCT, in whom alternative approaches
should be explored.
Therapeutic strategies for transplantable age patients
It is well established that TKI-based treatment, followed
by allo-SCT in CR1, is the gold standard therapy and
provides curative potential for adults with Ph + ALL.
Studies from several cooperative groups, have showed 3-year
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survival probabilities of 5570% in young adults
receiving IM-containing induction followed by myeloablative
allo-SCT [27,28]. And the survival is inferior in
nontransplanted patients, despite the inclusion of IM in the
protocols. More recently, the Northern Italy Leukemia
Group disclosed a long term results of patients who
were treated with chemotherapy plus short IM pulses.
In the study, the probability to receive an SCT was
significantly increased in IM + patients compared with
IM- cohort (63% vs. 39%, p = 0.04), indicating that
incorporation of IM to chemotherapy not only increase the CR
rate, but also increase the number of patients proceeding
to SCT. And patients receiving a SCT had the best
outcome (n = 58; 5-years OS 49%), while in those unable
to reach SCT, outcome was inferior (IM + SCT-: n = 17,
5-years OS 11%; IM-SCT-: n = 13, 5-years OS 8%),
indicating allo-SCT remain the best consolidation option
even in patients who achieve a good response to
TKIbased therapy .
Of note, there is increasing reluctance to offer allo-SCT
to younger patients in the TKI era, because younger
individuals usually have a better outcome to chemotherapy/
TKI alone and have more to lose by risking the
longterm adverse consequences of SCT. In a previous study,
Schulz et al. found that intensive chemotherapy plus
continuous IM improved survival rate for children and
adolescents, with minimal toxicities . And the 3-year
EFS was not significantly different for the patients
receiving chemotherapy/IM alone compared to those
proceeding to sibling donor SCT (88% 11% vs. 57% 22%).
This study suggested the outcomes were not superior
with allo-SCT compared with intensive chemotherapy
plus IM for a subgroup of younger patients. Recently,
Santhosh et al. also evaluated the feasibility of combining
IM with a pediatric-based regimen (a modified version of
the Dana Farber Cancer Institute protocol) for young
adults with Ph + ALL, in whom the complete response
rate was 94%. Of 16 patients who underwent allo-SCT in
CR1, six died of non-relapse complications. Based on
an intention-to-treat and time-to-donor identification
analysis, they did not find any significant difference
in either OS or EFS between transplanted and
nontransplanted patients .
Nevertheless, interpretation of these findings is limited
by the small patient numbers and the relative short
followup. Thus, it is difficult to answer whether IM/intensive
chemotherapy could replace allo-HSCT for younger
patients with Ph + ALL. However, these provocative data
open the way for further discussion. Future studies will
focus on development of independent prognostic algorism,
such as MRD at relevant time-points, to identify a
subgroup of good risk younger patients, eligible for receiving
treatment with chemotherapy and TKI only, and
accordingly sparing SCT.
Imatinib-based therapy in elderly patients
Ph + ALL accounts for 40 50% of ALL in patients over
50 years, many of whom cannot tolerate intensive
chemotherapy and are not eligible for SCT. The question of
whether minimization of therapy-related toxicity by
combining TKIs with less intensive chemotherapy yielded
equivalent results were proposed in this subgroup of
patients. Several studies showed IM combined with minimal
chemotherapy was able to yield a higher CR rate and
fewer deaths without major toxicity in elderly patients
than observed in historical controls. However, a main
problem of this less intensive approach is the very high
relapse rate, yielding an OS probability of less than 20%
in the studies with long-term follow-up . Dasatinib
is a dual BCR-ABL and Src kinase inhibitor with
approximately 325-fold greater activity than IM against
BCR-ABL, and with activity against most mutations
resistant to IM, with the exception of T315I, but to date,
it is still unknown whether dasatinib therapy is superior
to IM in terms of preventing relapse or inducing longer
EFS. Now, the European Working Group on Adult ALL
(EWALL) disclosed the final results of the combination
of dasatinib and a low Intensity chemotherapy
(vincristine and dexamethasone) for first-Line treatment in
patients with de novo Ph + ALL aged > 55 years . This
regimen was followed by chemotherapy and dasatinib
interspersed between the therapeutic cycles. Of the 71
subjects, 94% achieved a CR. At 3 years, relapse free
(RFS) and overall survival (OS) were estimated as 42.7%
and 44.7%, respectively. 29 patients relapsed after a
median of 9 months. Most relapses were associated with the
T315I mutation. And the presence of abnormalities
additional to t(9;22) were associated with a worse RFS.
To some extent, the 3-year OS at 44.7% for elderly patients
is quite encouraging, a result in the range of reported
survival in younger adults. This study also identified a
subgroup of elderly patients with poor prognosis, in whom
reduced intensity conditioning (RIC) or non-myeloablative
HSCT will be considered to perform as the consolidation
therapy. Other studies incorporated nilotinib or interferon
to the induction or consolidation therapy and tried to
determine whether these new regimen would improve
the results for the elderly, without increasing the
toxicity. An Italian trial enrolled 39 Ph + ALL patients
aged > 60 years or unfit for intensive chemotherapy and
SCT . They were treated with two TKIs (nilotinib
400 mg twice daily, and imatinib 300 mg twice daily),
alternating for 6 weeks for a minimum of 24 weeks.
Overall, one patient was primarily resistant and 13
patients relapsed, and the OS at is 64% at 2 years. Although
in this small cohort of elderly/unfit patients, the rates
of relapse and progression were not likely to be
different from the rates observed with imatinib alone 
and dasatinib alone , Its important to notice that
the mutations that occurred at the time of relapse were
sensitive to other TKIs (dasatinib and ponatinib).
Interferon as treatment for Ph + leukemia has attracted
renewed interest, fueled by preclinical observations that
IFN may recruit dormant CML stem cells into the cell
cycle, and enhance their susceptibility to eradication by
TKIs. More available clinical data come from the
treatment of CML. Recently, an open-label phase II study
was designed to investigate the combination of low-dose
IFN-alfa with IM as maintenance therapy (MT) in the
elderly with Ph + ALL patients . Maintenance therapy
consisted of IM at a single dose of 600 mg daily, combined
with low-dose subcutaneous interferon-alfa-2a starting
at 1 MU three times a week with dose escalation to a
target dose of 3 MU three times a week. Median overall
survival for patients (n = 7) receiving IM + IFN-alfa is
5.4 vs. 2.9 years for patients receiving IM alone (n = 12).
The patients receiving IM + IFN- alfa had a longer
median remission duration from start of maintenance
(2.2 years), compared with patients receiving IM as MT
(0.75 yrs, p = 0.07). The lack of relationship between
number of consolidation cycles and remission duration
suggests IM + IFN-a MT may be effective even if started
earlier during front-line therapy. Evaluation of the more
potent 2nd generation TKI in combination with
IFNalfa for Ph + ALL is warranted in future.
Administration of TKI after SCT
Minimal residual disease after allo-SCT for Ph + ALL is
predictive of relapse. Imatinib administration subsequent
to SCT may prevent relapse, but to date there is no
largescale prospective randomized control trial to provide
sufficient evidence to conclude that IM or other TKIs should
be given to all patients after SCT, even though small
studies suggested efficacy [38,39]. A single center study
from the University of Minnesota showed a trend toward
improved outcome in patients who could be treated
with IM in the pre- and post-transplant period following
myeloablative conditioning . Ram et al. also reported
that IM given for a median duration of 1 year after
RICSCT had good tolerability and was associated with an
improved outcome, although the effect on relapse was
not statistically significant . In a Chinese study, IM
treatment was scheduled for 312 months after SCT,
until BCR-ABL transcript levels were negative at least
for 3 consecutive tests or molecular remission was sustained
for at least 3 months. It was proven that administration of
IM after SCT could reduce the 5-year relapse rate (IM
group vs. non-IM group: 10.2% vs. 33.1%, p = 0.016), and
prolong the 5-year DFS. (IM group vs. non-IM group:
81.5% vs. 33.5%, p = 0.000) . Similarly in a Japanese
study, IM after allo-SCT also had a favorable impact on
The optimal time for initiating IM treatment following
SCT is not well established. The CSTIBES02 trial reported
that IM was poorly tolerated following myeloablative SCT:
only 62% were able to start at a median of 3.9 months
after SCT, and many patients required discontinuation or
dose reduction due to complications such as GVHD .
The GMALL study compared the tolerability and efficacy
of post-transplant IM administered either prophylactically
(to begin at 3 months after SCT) or following any
BCRABL reappearance. No significant difference in outcome
was observed between prophylactical IM or MRD-triggered
IM after SCT (5-year OS 82% vs. 78%, respectively).
However, more than half of enrolled patients discontinued
IM in both groups, predominantly owing to
gastrointestinal toxicities, indicating poor tolerance of IM when
given early after allo-SCT . In a recent study,
postSCT IM therapy was initiated if patient neutrophil counts
were >1.0 109/L and platelet counts were >50.0 109/L,
or if they displayed either elevated BCR-ABL transcript
levels in two consecutive tests, or a BCR-ABL transcript
level 10-2 after initial engraftment . In this design,
interruptions of IM therapy due to adverse events (AEs)
were relatively lower. Thus, careful consideration should
be given as to when to start IM, based on patient
BCRABL transcript levels, while concurrently taking into
account the clinical conditions of individual patients
(including engraftment and GVHD).
Experience on the use of dasatinib after HSCT is very
limited. A study by Caocci and colleagues suggested that
administration of dasatinib 120 days after SCT is highly
effective in preventing Ph + ALL relapse after both
autoand allo-SCT . However, another preliminary data
from Taiwan could not fully support this conclusion,
and extramedullary relapse could be problematic despite
provision of both allo-SCT and dasatinib . Prospective
and randomized studies for indentifying the appropriate
TKI scheme in Ph + ALL after SCT are urgently needed.
Future treatment to overcome TKI resistance
Despite high remission rate induced by TKI-containing
regimens, fewer than 50% of these patients sustain
molecular remission after initial therapy, and overt clinical
relapses are frequent, indicating that TKI resistance is a
substantial obstacle in Ph + ALL. The emergence of BCR
ABL mutations is the most important mechanism of
resistance to TKI. Mutations can occur within the A
(activation)-loop, the P (ATP-binding)-loop region or
at the so-called gatekeeper residue, threonine 315. Given
that the prognosis of patients with Ph + ALL with T315I
mutation is poor, many new agents have been clinically
investigated in the setting of T315I and other mutations.
Ponatinib is a pan-BCR-ABL inhibitor with activity against
all IM-resistant mutants, including the T315I mutation.
Ninety four patients with CML lymphoid blast phase or
Ph + ALL were included in the pivotal phase 2 study,
who were resistant or intolerant to other TKIs .
With a short median follow up of 2 months, the major
hematologic response were 37% and 27%, in patients
with resistance/intolerance to prior TKI and those with
T315I mutation, respectively. Treatment with ponatinib
was generally well tolerated, and thrombocytopenia and
neutropenia were the most common grade 3 or more
AEs. Thus, ponatinib combined with chemotherapy is a
promising approach to overcome TKI resistance. Other
new drugs such as Aurora kinases (AK) inhibitors 
and DCC-2036  have recently entered preclinical or
clinical testing, but more mature data are required.
New treatment approaches for Ph -negative acute
Although cure rates in pediatric ALL are now around
90%, there is still room for improvement in the
management of adult patients with Ph- ALL, where little progress
has been made over the past two decades and long-term
cure rates usually do not exceed 40%, even with allo-SCT
. Given the disappointing outcomes, there is a critical
need for developing new approaches to treating adults
with this disease, including the use of pediatric inspired
regimens and incorporation of novel targeted agents alone
or in combination with other chemotherapeutic drugs.
Application of pediatric inspired regimens to young adults
One of promising approaches in treating young patients
with Ph- ALL is adopting pediatric protocols - the so
called pediatric inspired regimens, especially for those
adolescent and young adult (AYA) aged 15 to 39 years.
Retrospective studies have shown that AYA with ALL
treated with pediatric-inspired regimens have better
outcomes than similarly aged patients with adult protocols,
and improved the event-free survival rate of newly
diagnosed Ph- ALL to 60% or higher . This compared to
35%40% for historical controls and without additional
benefit of SCT. However, prospective studies comparing
AYA adopting adult protocols with pediatric protocols
are rare. Recently, a Japan adult leukemia study group
conducted a phase II multicenter study to determine the
outcome of pediatric protocols for AYA with Ph- ALL
(Japan Adult Leukemia Study Group (JALSG) ALL202-U
study) . In comparison with the former JALSG
ALL-97 adult protocol, the pediatric protocols showed
an increase in cumulative dose of cyclophosphamide
(1.5-fold), vincristine (1.2-fold), L-asparaginase (18-fold)
and methotrexate (3.7-fold), respectively. As for the
intrathecal chemotherapy, the duration was longer and
the frequency was increased from 8 to 15 times. Of the
138 eligible patients, 134 patients (97.1%) achieved CR.
Compared with previous JALSG ALL-97 study, CR rate
(97.1% ALL202, 84% ALL97; p = 0.01), 4-year DFS rate
(71% ALL202, 46% ALL97; p = 0.0001) and 4-year OS rate
(74% ALL202, 46% ALL97; p = 0.0002) were significantly
higher in this pediatric protocols. Studies by groups in
other countries also yielded comparable results .
Although it is still unknown why treatment with pediatric
protocols resulted in improved outcomes, the disparity
may be explained by some common features of pediatric
treatment strategies, including (1) significantly
increasing the non-myelosuppressive agents such as vincristine
and steroids, (2) using much higher cumulative doses of
asparaginase (ASP) for prolonged asparagine depletion,
(3) administering very early and more frequent intrathecal
methotrexate together with very high-dose systemic
methotrexate, (4) including longer antimetabolite-based
maintenance cycles, and finally, (5) patients treated on pediatric
protocols are more likely to adhere to cycle start dates
and have shorter rest between cycles. Together, these
features may contribute to the improved outcomes for
young patients treated on pediatric protocols. However,
the outcomes for AYAs with ph- ALL still lag
significantly behind those achieved in younger children. Thus,
challenges for the future include identifying unique
aspects of drug pharmacology in young adults to refine
dosing schedules, and recognizing additional biologic
factors of AYA, with the anticipation that these discoveries
will provide new targeted therapeutic opportunities.
Novel and emerging drugs for ph-negative ALL
Classic treatment regimens using combination
chemotherapy are associated with substantial toxicities that
limit further dose escalation. Therefore, development of
new, targeted and less toxic agents, such as nucleoside
analogues and monoclonal antibodies (mAbs), offer
promise for improving the outcome of Ph- ALL.
New types of asparaginase
As mentioned above, young adults with ALL adopted
pediatric regimens, with prolonged use of ASP, mostly
E. coli, had better outcomes than historically reported.
Considering its potential higher toxicity, however, ASP
is either not used or given for much shorter duration,
particularly in patients aged > 45 years. Some new types
of ASP are emerging. The pegylated E. coli derived form,
PEG-ASP, is most commonly used, because it shows less
immune response and a prolonged half-life of 5.7 days
compared to 1.3 days for native ASP. The incorporation
of PEG-ASP in induction and especially during
consolidation therapy seems to improve the outcome with a
manageable and reversible toxicity [53,54] as shown in
several studies. However, clinical hypersensitivity
reactions still occur in 10-30% of patients requiring its
discontinuation. Asparaginase Erwinia Chrysanthemi (Erwinaze)
is an L-ASP derived from a different bacterium and is
immunologically distinct from the E. coli L-ASP. Plourde
et al. conducted a compassionate use trial of Erwinaze in
1368 ALL patients with hypersensitivity to native E. coli
or PEG-ASP to collect safety information . 77.6% of
patients were able to complete their Erwinaze treatment.
Discontinuation due to allergic reaction occurred in 8.8%
and other AEs in 4.7%. The study suggested Erwinaze
was well tolerated with no unexpected toxicities
identified beyond those associated with L-ASP treatment. In
addition to Erwinaze, L-asparaginase-loaded red blood
cells (GRASPAW) has been a new available option for
ALL population, including older patients with the disease.
In a randomized trial from France, the use of GRASPA in
refractory or relapsing ALL showed a reduction in the
number and severity of allergic reactions and a trend to
fewer coagulation disorders . Another phase II dose
escalation study aimed at determining optimal dose of
GRASPA that could be combined with standard EWALL
chemotherapy backbone in patients aged >55y with newly
diagnosed Ph- ALL . The study indicated that GRASPA
at a dose of 100 UI/kg infused twice during induction
cycles, appears to be the best manner with sustained
asparagine depletion and a good efficacy/safety profile,
and the dose of 100 IU/kg was associated with median
OS of 15.6 months, compared favorably with
Recently, the development of monoclonal antibodies has
provided hope that tumor-targeted therapy would one
day play a role in the treatment of ALL with less
systemic toxicity profile . To date, the most data are
available for anti-CD20 (rituximab), which has been
combined with chemotherapy for the treatment of B-lineage
ALL or Burkitt lymphoma . In an update of study
from M. D. Anderson, 216 pts with Ph- B-lymphoblastic
leukemia have been treated with the modified
hyperCVAD regimens with or without rituximab . For the
younger (age < 60 years) CD20-positive subset, rates of
complete remission duration (CRD) and OS were better
with the combination of hyper-CVAD plus rituximab than
with hyper-CVAD alone (69% v 38%; P < .001% and 71% v
47%, P = .003). However, in contrast to the Burkitt
experience, no benefit from the addition of rituximab
was noted in elderly patients (age > = 60 years), in
part because of deaths in CR from infections during
consolidation. A similar outcome was also observed in
CD20+ Ph- B-precursor ALL from the German GMALL
7/03 study . In their study, among patients younger
than 55 years, the addition of rituximab was associated
with a 5-year survival rate of 71% versus 51% without
rituximab. These studies suggest that rituximab added
to intensive chemotherapy has improved the outcome
for CD20-positive B-lineage ALL, particularly among
younger adults. Further investigation will address the
role of extended rituximab therapy with attenuated
chemotherapy (to reduce risk of infectious complications) in
older patients. And studies combining chemotherapy with
ofatumumab or with other more potent CD20 monoclonal
antibodies such as GA-101 are also warranted [59,62,63].
Another actively investigated MoAb is anti-CD22.
Epratuzumab, the naked humanized MoAb against CD22,
was first studied in children with relapsed ALL showing
minimal single-agent activity . For adult patients, a
phase II study through the Southwest Oncology Group
(SWOG) is ongoing and presenting some findings. They
found giving epratuzumab together with cytarabine and
clofarabine improving response rate (to 45%) in patients
with relapsed/refractory (R/R) precursor B-ALL, and thus
warrants further testing . Inotuzumab ozogamicin, a
CD22 monoclonal antibody bound to calicheamicin, is
also active in ALL. In a phase II study of inotuzumab 1.3
to 1.8 mg/m2 IV once every 3 to 4 weeks in 49 patients
with R/R B-lineage ALL, the overall response rate was 57%
and the median survival of all patients was 4.5 months.
Given the heavily pretreated patients, the response rate in
R/R ALL was promising and twenty-two of the 49 patients
were able to proceed to subsequent allo-SCT. The most
common adverse effect was liver function abnormalities
that were severe in 31% of the patients . Recently
inotuzumab was delivered at smaller doses and a more
frequent schedule (inotuzumab weekly, 0.8 mg/m2 D1,
0.5 mg/m2 D8 and 15, q3-4 weeks) than previously
studied. The modified schedule appears to be equally
effective with response rate of 53% and median survival
of 6.3 months, and it is less toxic than single dose,
indicating this weekly schedule might be superior to single
dose schedule .
Bi-specific MoAbs constitute a new generation of
compounds with a promising future. In a recent phase II trial,
blinatumomab, a bi-specific MoAb with a CD3-binding
site for the T cells and a CD19 site for the target B cells
, has been highly effective in treating adult
Bprecursor ALL in hematological CR but with molecularly
persistent or relapsed disease (MRD positive) . More
recently, blinatumomab was investigated in adults with
active refractory/relapsed ALL. In an ongoing study, 36
adult patients received blinatumomab at three dosing
regimens. Twenty six patients (72%) achieved a
hematological CR or CR with partial hematological recovery, 24
of whom were MRD negative within the first 2 cycles.
These results revealed blinatumomab may become the
most effective new single targeted agent so far developed
for B-lineage ALL. And side effects, including cytokine
release syndrome and CNS events were manageable
and reversible. As final dose and schedule, 5 g/m2/day
in week 1 and 15 g/m2/day for week 24 was selected
for further investigation based on safety/efficacy
Other potential new agents
In addition to mAbs, other potential new agents are
mammalian target of rapamycin (mTOR) inhibitors, JAK
inhibitors  and the purine analogs. In T-ALL,
attention must be paid to the novel purine analogs such as
clofarabine, forodesine, and, especially, to nelarabine .
The latter drug has proven to be active in relapsed/
refractory disease , and is being evaluated in
combination with hyper-CVAD for newly diagnosed T-ALL
Improvement in SCT for ph-negative ALL
Allogeneic SCT is the most potent postremission
antileukemic therapy in ph- adult ALL, with OS rates
exceeding 50%. Several older randomized trials and meta-analyses
concluded that high-risk, not standard-risk, patients
benefited from allogeneic SCT in CR1 . Modern protocols
tend to avoid SCT in standard-risk patients who are
confirmed to be MRD-negative given the excellent
results of pediatric-based chemotherapy. However, two
recent randomized trials from MRC-ECOG and JALSG
give an opposite conclusion that the statistically significant
survival advantage with allo-SCT appears to be greater for
patients with standard-risk rather than high-risk ALL
patients, a finding that likely reflects the increased
treatmentrelated mortality (TRM) in the high-risk (especially older)
patients that negated the GVL effect in these patients
[49,76]. It is noted that inclusion of the younger patients
in the two randomized trials may have biased the results
in favor of allo-SCT, and therefore ongoing reassessment
of the place of allo-SCT needs to be continued.
The increasing use of unrelated donors, umbilical cord
blood (UCB), haploidentical donors, and reduced intensity
SCT have expanded the opportunity for more patients
to undergo SCT. The OS rate of unrelated donor
(URD)SCT are currently close to those for related donors;
the higher transplant-related mortality of the former is
counterbalanced by the lower relapse rate .
Development of high-resolution HLA typing technology will
further improve the transplant outcome for URD-SCT.
UCB has emerged as a major, untapped source for SCT,
providing clinicians and patients with increased choices
for alternative donors. The use of less well-matched UCB
grafts has yielded equivalent results as 8/8 and 7/8 URD
allele-matched grafts, enhancing the appeal of this product
. Although haploidentical SCT remains
investigational, this approach has shown promise when used in
conjunction with high-dose posttransplantation
cyclophosphamide in patients with very high-risk ALL who
lack an unrelated donor [79,80]. Finally, RIC facilitates
SCT in elderly patients and those who have comorbid
conditions. It is shown that RIC-SCT is associated with
comparable donor engraftment rates and lower incidences
of TRM, but with higher relapse rates than myeloablation.
Thus, OS rates are similar to myeloablative conditioning.
Given the negative inherent patient selection criteria bias,
RIC-SCT could actually prove to be superior. Autologous
SCT has a low antileukemic effect in adult ALL, but could
be active in certain situations such as MRD negativity after
Despite outstanding advances in the knowledge of the
molecular basis of adult ALL, the treatment of this disease
remains challenging. Improvements in the outcome of
ALL have been observed in young adults as a result of the
use of inspired regimens and the broadening of the
number of patients who are eligible for allogeneic SCT, whereas
the prognosis of the elderly remains poor. Development of
new and less toxic agents provide promise to improve the
outcome in adult ALL, such as tyrosine kinase inhibitors
in Ph-positive ALL, rituximab in CD20-positive disease,
blinatumomab in precursor B-ALL and nelarabine in
Tlineage ALL. From the biological prospective, genetic
profiling approaches will provide a comprehensive view
of the complexity of genetic alterations in ALL.
Identifying miRNAs, genes, and pathways relevant for the
pathogenesis of the leukemia and the biologic determinants of
treatment failure may provide novel insights on novel
targets . However, these findings should be brought from
bench to bedside for novel targeted therapies.
GW participated in concept design and critically revising the manuscript. YZ
participated in data collection and drafting the manuscript. HH participated
in reviewing and revising the manuscript. All authors have read and
approved the final manuscript.
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