Review Article
Recent Developments in Immunotherapy for Acute Lymphoblastic Leukemia
Bonifacio M*, Tanasi I and Krampera M
Department of Medicine, University of Verona, Italy
*Corresponding author: Massimiliano Bonifacio, Department of Medicine, Section of Hematology, University of Verona, P.le L.A.Scuro 10, 37134 Verona (IT), Italy
Published: 25 Jul, 2016
Cite this article as: Bonifacio M, Tanasi I, Krampera
M. Recent Developments
in Immunotherapy for Acute
Lymphoblastic Leukemia. Clin Oncol.
2016; 1: 1025.
Abstract
Despite high rates of initial response to frontline therapy, the prognosis of adult patients with acute
lymphoblastic leukemia (ALL) is still unsatisfactory, as many of them fail to reach a stable complete
molecular response and they ultimately relapse. Intensification of chemotherapy regimens has
determined a survival improvement especially in younger patients, but this strategy is less effective
in case of unfavourable, high-risk cytogenetics and it is not feasible in unfit patients.
The number of target therapies for ALL patients has rapidly increased in the recent years. In particular,
the use of drugs targeting either CD19 (blinatumomab and Chimeric Antigen Receptor-T cells) or
CD22 (inotuzumab ozogamicin) led to unexpected high rates of deep/complete molecular response
also in patients with relapsed/refractory disease after several lines of treatment, including allogeneic
hematopoietic stem cell transplantation (HSCT). Unfortunately, this huge degree of response has
determined so far only a small improvement of survival due to the short duration of remission,
in particular when early consolidation with HSCT could not be performed. Early employment of
immunotherapy, either at diagnosis or at first remission, seems a promising strategy to be tested in
future prospective trials.
Keywords: Leukemia; Immunotherapy; Lymphoblastic
Introduction
Acute lymphoblastic leukemia (ALL) is a heterogeneous disease arising from the malignant
transformation and uncontrolled clonal expansion of early lymphoid progenitor cells [1].
Depending on the cell of origin, ALL are classified in B-cell precursor (BCP) and T-lineage subtypes.
While long-term survival in children exceeds 80%, prognosis of adult patients still remains less
satisfactory, with 40-50% overall survival (OS) and disease-free survival (DFS) rates also in recent
years [2,3]. Actually, the majority of patients achieve complete response (CR) after frontline
treatment; however, many of them either fail to reach a complete molecular response or relapse,
often with a chemoresistant disease, thus showing typically poor OS [4,5]. The incorporation of
intensive, pediatric-inspired chemotherapy regimens in the treatment of adult ALL has led to
survival improvements as compared to historical controls [6,7]. However, it is very unlikely that the
sole intensification of chemotherapeutic regimens can continue to improve prognosis substantially,
particularly in elderly patients where a successful treatment is hampered by the poor tolerance of
intensive regimens and the difficulty to perform allogeneic hematopoietic stem cell transplantation
(HSCT) [8].
In the last decades, cytogenetic and molecular studies unraveled partially the biological
complexity of ALL, indicating the leukemogenic role of recurrent abnormalities and identifying
in some cases novel prognostic markers and molecular targets [9]. Unfortunately, excluding the
substantial therapeutic improvements of tyrosine kinase inhibitors in Philadelphia chromosome
(Ph)-positive ALL [10,11], target drugs are still unavailable for most of the newly defined molecular
ALL subtypes. In this setting, immunotherapy represents a promising treatment strategy, because
surface target molecules are expressed in the vast majority of ALL patients and novel immunological
agents display a distinct, generally mild, toxicity profile that does not overlap chemotherapy.
Here we will review the role of immunotherapy in ALL, with a particular focus on the efficacy
data in the higher risk subsets, i.e. elderly or relapsed/refractory patients.
The Role of Immunological Control in ALL
The role of the immune system in the control of tumorigenesis was preliminarily shown in 1891 by William Cooley, who developed the first successful immunotherapy against cancer by injecting streptococcal cultures to cure sarcoma patients. At present, it is known that the immune system plays an ambivalent role, both suppressing and promoting the growth of cancer cells, thus favouring their escape from the immune-mediated clearance through several mechanisms (e.g. loss of MHC I, reduced antigen expression, development of immunosuppressive microenvironment, etc.) [12]. However, the definite curative role of HSCT in a subset of refractory cancers, including ALL, witnesses the possibility to overcome the immunotolerance state induced by cancer cells. The concept of eliciting an anti-tumor, post-transplant immunological effect, i.e. graft-vs.-leukemia (GvL), has been shown first in ‘70s [13] and extensively documented in ALL patients [14,15], leading to the use of donor lymphocyte infusions (DLI) to treat leukemic relapse after HSCT [16]. Various mechanisms have been hypothesized to explain GvL, including the reversibility of T-cell exhaustion (i.e. the reactivation of quiescent T cells immunosuppressed by the chronic exposure to tumor antigens) and the interaction with tumor-specific antigens or aberrant proteins [17]. Although the GvL effect in ALL is less potent than in myeloid leukemias [18], there is clear evidence for a T cell-mediated GvL against minor histocompatibility antigens or self-antigens, such as the Wilms Tumor Antigen-1 (WT1) [19,20]. A preventing DLI strategy seems to be more effective than salvage therapies for overt relapse: 16 patients (8 ALL) who became molecularly positive after HSCT were treated with pre-emptive DLI and had 100% CR rate with 1-year OS of 93.8%, significantly higher than that obtained in a comparison cohort of 11 patients (3 ALL) treated with DLI in overt relapse (CR rate 63.6% and 1-year OS 27.3%) [21]. Many efforts are still addressed to separate GvL from Graft-versus-Host Disease (GvHD) effect, in order to maximize the antitumor alloreactivity while limiting acute and chronic toxicity.
Table 1
Monoclonal Antibodies in ALL
The use of monoclonal antibodies in ALL has rapidly grown in
recent years [22]. Lymphoblasts express several antigens in a quite
specific manner and/or at higher density on their cell surface as
compared to normal lymphocytes, thus allowing a selective membrane
targeting and cell killing (Table 1). There are four categories of
monoclonal antibodies that are currently available for ALL: a) naked
antibodies killing the target cells through antibody-dependent
cell-mediated cytotoxicity (ADCC) (e.g. rituximab, ofatumumab,
alemtuzumab, epratuzumab); b) antibody-drug conjugates and
c) antibody-immunotoxin conjugates, which exert their cytotoxic
effect by vehiculating against the target cells either chemotherapeutic
agents (e.g. inotuzumab ozogamicin and denintuzumab mafodotin)
or natural toxins (such as Pseudomonas aeruginosa or diphtheria
toxin) (e.g. moxetumomab pasudotox), respectively; and d) bispecific
T-cell engager (BiTE) antibodies tethering autologous resting
T lymphocytes to cancer cells, which in turn trigger T cell-mediated
oncolytic functions (e.g. blinatumomab) [23]. Chimeric antigen
receptor (CAR) T cells are often joined to anti-CD19 antibodies in
many reviews, but they represent a substantially different treatment
strategy: although CD19 is the only available target of CAR T-cells
so far, this technology might be applied to many other antigens:
therefore, they will be reviewed in a separate chapter.
Anti-CD19 monoclonal antibodies
Nearly all cases of BCP ALL display a bright expression of CD19
[24], making this marker an ideal candidate for target therapy.
However, the cellular internalization of CD19 when bound by specific
antibodies and the poor results described in the first studies with
naked anti-CD19 compounds have hampered the development of
therapeutic naked anti-CD19 antibodies [25]. New hints came from
the development of anti-CD19 antibodies conjugates with cytotoxic
drugs (denintuzumab) or toxins (Combotox, SAR3419), and above
all from the novel BiTE technology (blinatumomab).
Denintuzumab mafodotin (SGN-CD19A): Denintuzumab
mafodotin, formerly indicated as SGN-CD19A, is a humanized anti-
CD19 monoclonal antibody conjugated to the powerful monomethyl
auristatin F (MMAF), a microtubule-disrupting agent, which is
released directly into the target cells upon CD19 internalization. A
phase 1 study has recently closed the enrollment of adult and pediatric
patients with R/R BCP ALL, Burkitt leukemia/lymphoma, and
B-lineage lymphoblastic lymphoma (n=91). A preliminary analysis
on 49 patients (40 with BCP ALL) showed a 30% response rate, with
6 out of 8 CR/CRp patients achieving a complete MRD response.
No responses were observed in pediatric patients or in patients with
Burkitt leukemia/lymphoma. AEs associated with denintuzumab
treatment included severe kerathopaty in 4 adult patients, partially
reduced by prophylactic steroid eye drops [26].
Combotox and coltuximab ravtansine: Combotox is a mixture
of antibodies targeting both the CD19 and CD22 antigens, conjugated
with a deglycosylated ricin A chain. A phase 1 study demonstrated
transient responses in adults [27] and this agent is currently evaluated
in combination with chemotherapy for the treatment of patients with
R/R BCP ALL. Coltuximab ravtansine (also known as SAR3419) is a
humanized anti-CD19 antibody conjugated with maytansin, a potent
microtubule inhibitor. In a phase 2 study in relapsed BCP ALL (n=36)
SAR3419 was well tolerated, although associated with a small clinical
response rate (about 25%, with a median duration of response of only
1.9 months); consequently, the study was prematurely discontinued
and this agent was no longer developed for ALL therapy [28].
Blinatumomab: Blinatumomab is a first-in-class BiTE antibody
that engages cytotoxic CD3+ T-cells and drives them in contact
with CD19+ cells [29]. First description of blinatumomab activity
in humans involved 38 patients with relapsed Non Hodgkin’s B-cell
lymphoma: tumor regression occurred in a dose-dependent manner,
and blinatumomab doses as low as 15 μg/m2/day led to depletion of tumor cells in the majority of bone marrow infiltrates, while higher
doses were required to obtain measurable effect on lymph nodes
[30]. This observation paved the way for the further development
of blinatumomab-based strategies in the treatment of BCP ALL.
Table 2 summarizes the available evidence of the clinical activity of
blinatumomab in different settings.
Blinatumomab in MRD-positive BCP ALL: In a phase 2 pilot
study on 21 patients with B-ALL in complete hematologic remission
(CHR) but MRD persistance or MRD relapse (>10-4), blinatumomab
was administered at a fixed dose of 15 μg/m2/day 4 weeks on and
2 weeks off, until a maximum of 4 cycles. Sixteen of 20 evaluable
patients (80%) obtained a complete MRD response after 1 cycle of
blinatumomab, without differences between patients with MRD
persistance or relapse [31]. After blinatumomab treatment, 9 patients
underwent allogeneic HSCT and 11 did not: relapse-free survival
(RFS) at a median observation of 33 months was 65% in transplanted
patients and 60% in non-transplanted patients, respectively. Of note,
two late relapses (19 and 31 months after treatment, respectively)
were observed in transplanted patients, while no further relapses
were documented after more than 7 months from blinatumomab
treatment in patients not undergoing HSCT [32].
A confirmatory multicenter phase 2 study (BLAST study) was
carried out to evaluate the rate of complete MRD response after
one cycle of blinatumomab. Inclusion and exclusion criteria were
similar, but patients were required to have a higher MRD load (≥10-
3). The primary endpoint of the study was achieved by 88 out of 113
evaluable patients (78%) and 2 additional patients obtained complete
MRD response after more than 1 cycle of blinatumomab. MRD
response was achieved by all subgroups, irrespectively of gender,
age, number of prior relapses and MRD level at study entry [33].
However, patients treated in first CR had longer RFS than patients
treated in later remission (median 24.6 vs. 11 months, respectively).
After blinatumomab treatment, 90 patients underwent HSCT and
26 did not: no differences were observed in OS and RFS between
transplanted and non transplanted patients [34].
Blinatumomab in relapsed-refractory BCP ALL: A dose-finding
phase 2 study was conducted by the GMALL group on 36 patients
refractory to chemotherapy (n=3), or relapsed after induction and
consolidation (n=18) or after HSCT (n=15). CR or CR without
hematological recovery (CRh) were reached by 25 out of 36 patients
(69%) and 22 of them also achieved MRD negativity, the majority
after one cycle of treatment. A non statistically significant higher rate
of CR/CRh was observed among patients in first salvage (100%) as
compared to patients in second or greater salvage (60%) or relapsed
after HSCT (53%). A dose-step strategy (5 μg/m2/day for the first
week of the first cycle, 15 μg/m2/day thereafter) was found to be safer
and was chosen for the subsequent blinatumomab studies [35].
These results were confirmed in a large international multicentric
study, including 189 patients with R/R BCP ALL at very high risk of
unfavourable outcome (primary refractory, relapsing after less than
12 months from first remission, in second or subsequent salvage, or
relapsing less than 12 months after HSCT). Patients should have more
than 10% bone marrow (BM) blasts at the time of blinatumomab
start. The primary endpoint of the study was CR/CRh after 2 cycles
of blinatumomab and was achieved by 81 patients (43%). Of note, the
probability of response was higher in patients with < 50% BM blasts
than those with ≥50% BM blasts (73% vs. 29%, respectively), while
no differences in response were observed according to gender, age
groups, previous lines of salvage or HSCT. After CR/CRh, 32 patients
underwent HSCT, with a transplantability rate of 40%. Median RFS
for patients in CR/CRh was 5.9 months and median OS 6.1 months
[36].
Following these results from phase 2 studies, blinatumomab
reached approval by the U.S. Food and Drug Administation
(expedite) and by the EMA agency (conditional) for the treatment
of Ph-negative BCP R/R ALL. Results of a randomized phase 3 study
comparing blinatumomab to standard of care (SOC) chemotherapy
were recently reported. A total of 405 patients were randomized in
a 2:1 ratio to blinatumomab (n=271) or SOC (n=134). Median OS
was significantly superior in patients randomized to blinatumomab
than to SOC (7.8 vs. 4.0 months, respectively) and the study was
prematurely stopped because of efficacy. Improvement in OS was
consistent between subgroups based on age, prior salvage therapy and
prior allogeneic HSCT [37].
Blinatumomab has been also tested in Ph-positive ALL patients
relapsed after, or refractory to, at least one second generation (2G)
TKI, or intolerant to 2G TKI and intolerant or refractory to imatinib.
The primary endpoint of CR/CRh after 2 cycles of blinatumomab was
met by 16 patients (36%), with similar response rates among patients
with or without the T315I mutation, and in patients previously treated with ponatinib. Similarly to Ph-negative R/R high risk patients,
median RFS for patients in this cohort was 6.7 months and median
OS was 7.1 months [38].
Blinatumomab in untreated BCP ALL: The ECOG group
designed a randomized phase 3 study to compare blinatumomab to
standard consolidation/maintenance chemotherapy after induction/
intensification chemotherapy in newly diagnosed Ph-negative ALL
patients aged 30-70: the study is ongoing (NCT02003222). Another
trial about frontline treatment of elderly patients with blinatumomab
in combination with low-dose chemotherapy or dasatinib in Phnegative
or Ph-positive patients is ongoing (NCT02143414).
Similarly the GIMEMA group has planned a trial with dasatinib and
blinatumomab in newly diagnosed adult Ph-positive ALL (D-ALBA,
NCT02744768).
Blinatumomab in special populations (pediatric and older
patients): In the pediatric setting, a phase 1/2 study was conducted
by the BFM and Children’s Oncology Group involving children with
primary refractory disease, in second or greater BM relapse, or in BM
relapse after allogeneic HSCT. Also in children, a dose-step approach
was found to be safer to prevent cytokine release syndrome (CRS). CR
rate was 31%, and 42% of responding patients reached also complete
MRD response. Half of the responder patients underwent allogeneic
HSCT, thus suggesting that blinatumomab can provide a bridge to
transplant also in children who are resistant to salvage chemotherapy
[39].
Recently, a pooled analysis of the phase 2 studies of blinatumomab
in R/R patients according to patient age at screening was reported:
of 36 adults older than 65 years (13.8% of all treated patients), 56%
achieved CR/CRh compared to 46% of younger adults, and the
rates of complete MRD response were comparable (60% and 70%,
respectively). Despite a significantly inferior use of allogeneic HSCT
in older patients, survival curves for RFS and OS overlapped for
both age groups. A higher incidence of severe neurologic events
was reported in older adults [40]. Similar rates of response between
patients younger or older than 65 years were also reported in the
confirmatory multicenter trial on MRD-positive patients [33], and in
the R/R Ph-positive trial [38].
Blinatumomab safety: Common toxicities after blinatumomab
administration included: pyrexia (81-88%), headache (38-47%),
tremor (29-36%), chills (25%), fatigue (24-50%), nausea (22%)
and vomiting (22%), severe lymphopenia (19%), and decrease of
immunoglobulin serum levels. Fatal cases of infections occurred
during or after treatment with blinatumomab, mainly in R/R nonresponder
patients [36]. Neurotoxicity represents the most significant
treatment-emergent adverse event (AE) associated to blinatumomab
treatment. Patients with history of either CNS relevant pathologies,
autoimmune disease or CNS leukemic involvement were excluded
from blinatumomab clinical trials. Neurologic events (including
tremor, dizziness, confusion, ataxia, aphasia, and seizures) tipically
appeared during the first days of treatment and in the majority of
cases were low-grade, reversible and did not preclude the possibility
of favourable responses [36]. However, CNS AEs were the main cause
of treatment interruption in 31% and 15-17% of patients in MRD
and R/R clinical trials, respectively. Stepwise dosing during the first
course and a mandatory pre-phase with high-dose dexamethasone in
cases of high tumor burden led to the reduction of both frequency
and severity of neurotoxicity. Anticonvulsivant prophylaxis was
reported to be effective in preventing further events in patients who
interrupted blinatumomab for seizure, and in many cases these
patients were able to resume blinatumomab treatment [35].
Anti-CD20 monoclonal antibodies
CD20 antigen expression on the surface of BCP ALL blasts is
quite heterogeneous, ranging from 0% of pro-B to 30-40% of pre-B
ALL cases and 100% of mature B-ALL [24]. Notably, its expression
increases after corticosteroid treatment and in patients with persistent
MRD after induction [41]. Two naked antibodies, rituximab and
ofatumumab, have been used in ALL, while there are only preclinical
data about obinutuzumab, another second-generation anti-CD20
antibody [42].
Rituximab: Rituximab is a type I chimeric monoclonal antibody
inducing cell lysis through a complement-mediated mechanism as
well as ADCC. Rituximab has no role as single agent in ALL, but some
studies have explored its activity in combination to chemotherapy.
The addition of 8 doses of rituximab (375 mg/m2) to the first 4 cycles
of HyperCVAD chemotherapy (fractionated cyclophophamide,
vincristine, doxorubicine and dexamethasone, alternating with highdose
cytarabine and methotrexate) improved the prognosis of CD20-
positive BCP ALL as compared to historical controls, but this benefit
was observed only in younger patients: 3-year rates of CR duration
in patients aged < 60 years were 70% vs. 38% for rituximab vs. no
rituximab patients, respectively, with a strong benefit in survival
(3-years OS 75% vs. 47%, respectively), while no improvement in the
outcome of older patients was found, mainly due to the increased fatal
infection rate in CR during consolidation [43]. In a GMALL study,
patients with CD20-positive newly diagnosed BCP ALL (age 15-55
years) were treated with (n=181) or without (n=82) the addition
of rituximab to induction and consolidation therapy: although
no differences were seen in the CR rate, there was a significantly
higher rate of MRD complete response in patients treated with
rituximab (90% vs. 9%), leading to improved 5-year OS (75% vs.
54%, respectively) [44]. The final results of a phase 3 randomized
study of the French GRAALL group were reported at the American
Society of Hematology (ASH) Meeting 2015: 209 patients with CD20-
positive BCP ALL at diagnosis (median age: 40 years) were randomly
assigned to receive a pediatric-like intensive induction/consolidation
chemotherapy with or without rituximab (16 to 18 doses). CR
rate and MRD response after induction and first consolidation
blocks were similar in the two study arms. At a median follow-up
of 30 months, relapse incidence was lower in patients treated with
rituximab (18% vs. 30%), translating in a significantly higher 2-year
EFS (65% vs. 52%, respectively). However, 2-year OS was not different
in the two groups and was superior in the rituximab arm only when
censoring for HSCT in first remission [45]. Of note, rituximab is
also commonly used in addition to chemotherapy for mature B-ALL
(Burkitt’s leukemia). Even though in many reports the improvement
of rituximab addition over rituximab-free chemotherapy regimens
has been poorly significant [46-48] or not detected at all [49], a recent
randomized phase 3 trial showed that the addition of rituximab to
short intensive chemotherapy improved 3-year EFS in adults (n=260)
with Burkitt’s leukemia or lymphoma (75% in the rituximab vs. 62%
in the no rituximab group) [50].
Ofatumumab: Ofatumumab is a second-generation anti-CD20
monoclonal antibody that binds to a different epitope on the target
antigens as compared to rituximab, thus increasing efficacy of
complement activation and ADCC. In a phase 2 study, ofatumumab
has been tested as frontline therapy of 41 patients with CD20-positive BCP ALL in association with HyperCVAD chemotherapy. Eight
doses of ofatumumab were administered during the first 4 cycles.
All but one patient achieved CR (97%) and 38 out of 40 responders
(95%) had a complete MRD response. With a median follow-up of 15
months, the 2-year PFS and OS rates were 68% and 87%, respectively
[51].
Anti-CD22 monoclonal antibodies
CD22 is expressed on the majority of B-cell malignancies,
including more than 90% of cases of BCP ALL [52], while it is not
expressed by stem cells and plasma cells. CD22 is an attractive target
for antibody therapy, because it is not shed in the extracellular
compartment and is internalized with high efficiency [53].
Inotuzumab ozogamicin: Inotuzumab ozogamicin (InO) is
an anti-CD22 directed antibody conjugated with calicheamicin, a
natural anti-tubulin cytotoxic drug, previously used also in the anti-
CD33 antibody-drug conjugate gemtuzumab ozogamicin. When
internalized upon CD22 binding, InO is rapidly degraded in the
lysosomes; calicheamicin is then released into the target cell and
moves to the nucleus, where it causes breaks in double-stranded
DNA and cell apoptosis [54].
Table III summarizes the available evidence about the clinical
activity of InO in different settings.
Inotuzumab in relapsed-refractory BCP ALL: A singleinstitution
phase 2 trial at the MD Anderson Cancer Center involved
90 patients (children were included) in first or later salvage therapy.
In a first cohort of 49 patients InO was given every 21-28 days
as single dose of 1.8 mg/m2 in adults and 1.3 mg/m2 in pediatric
patients, respectively. The overall response rate (including patients
with marrow CR without hematologic recovery) was 57%, without
significant differences among patients in first, second or further
salvage therapy (69%, 46%, and 67%, respectively). The majority of
responders (19/28, 68%) obtained the MRD-negative status. Median
survival was 5.1 months in the whole cohort and 7.9 months in the
responding patients; of note, survival was similar among patients
who underwent SCT or those who did not [55]. In a second cohort
of 41 patients, InO was administered on a weekly schedule (0.8 mg/
m2 on day 1, 0.5 mg/m2 on day 8 and 15 of a 21- or 28-day cycle),
which resulted in similar response rate and improved safety profile.
The median duration of response was 7 months, and 37% of patients
treated in first salvage line were alive at 1 year [56]. Patients with
high peripheral blast count, low platelet count or poor karyotype
[complex, t(9;22), t(4;11), and abn(17)] had a lower chance of CR and
shorter OS [57].
The relevant activity of InO in R/R patients was confirmed by a
multicenter phase 1/2 study in a particularly unfavourable population
of patients in second or later salvage line: overall remission rate (CR/
CRh) was 66% and median OS was 7.4 months [58].
Patient enrollment in a large randomized trial comparing InO with
standard chemotherapy in patients with BCP ALL in first and second
salvage line has been completed, and results of a preliminary analysis
on the first 218 randomized patients have been recently published
[59]. CR/CRi rate was significantly higher in patients treated with InO
as compared to standard chemotherapy (80.7% vs. 29.4%; p< 0.0001);
similarly, the rates of MRD negativity were significantly different in
the two arms (78.4% vs. 28.1%, respectively; p< 0.0001). In subgroup
analyses according to the patients’ characteristics at baseline,
the rate of response was better with InO as compared to standard
chemotherapy for all the factors examined, except for the Ph-positive
or t(4;11)-positive patients. Although the duration of remission
(4.6 vs. 3.1 months) and PFS (5.0 vs. 1.8 months) were significantly
longer for InO-treated than standard chemotherapy-treated patients,
median OS was only slightly better for the InO group (7.7 months vs.
6.7 months, respectively; p=0.04) and the second primary objective
of the trial (showing significantly longer OS in the InO arm) was not
met. However, a significantly higher percentage of patients were able
to proceed to SCT after treatment with InO as compared to patients
receiving standard chemotherapy (41% vs. 11%) and further followup
is required to determine the clinical benefit of InO treatment.
Inotuzumab in untreated BCP ALL: InO was combined with
low-dose HyperCVD regimen (omission of anthracyclines, reduction
of cyclophosphamide and steroids to 50% of the original dose, and
reduction of methotrexate and cytarabine to 25% of the original dose)
in untreated B-ALL elderly patients. InO was administered at single
dose of 1.3 to 1.8 mg/m2 with each of the first 4 courses, in addition
to rituximab standard dose. In 34 newly diagnosed B-ALL patients
(median age 69 years, range 60-79 years) the overall response rate
was 97%, and all the responding patients achieved MRD negativity.
The 2-year PFS and OS rates were 87% and 70%, respectively. These
results were better than those achieved with full dose chemotherapy
in a similar patient population (2 year OS 38%) and paved the way
to a broader use of InO and “mild” chemotherapy in the frontline
setting [60].
Inotuzumab in elderly patients: In the phase 3 INO-VATE trial
comparing InO to standard chemotherapy as salvage treatment, 38%
of patients were older than 55 years. Response rates in the InO arm
were similar for older and younger patients (CR/CRi rates 81.4% and
80.3%, respectively), and also the rates of MRD negativity among responders were not different (85.7% and 73.6%, respectively).
Cytopenias were more common in older patients. Overall, the
frequency of hepatic toxicities with InO was similar in all the age
groups, but VOD was more common in older than in younger
patients undergoing SCT following InO administration (33% vs. 17%,
respectively) [61].
Inotuzumab safety: Transient myelosuppression, abnormalities
in liver function tests, nausea, vomiting, abdominal pain, and fatigue
are the most common toxicities reported during treatment with InO.
Infusion-related reactions, including cytokine release syndrome,
have been observed mainly during the first cycle. An increased risk of
hepatic VOD was recognized as an emerging AEs potentially linked to
InO, occurring in 8-23% of patients both during and after treatment
with InO, also in non transplanted patients. Hepatic VOD has been
also associated with the use of anti-CD33 calicheamicin-conjugate
drug gemtuzumab ozogamicin, in CD33-positive acute myeloid
leukemia patients [62]. In InO-treated patients, VOD was associated
with more lines of therapy and more intensive myeloablative regimens
[63]. Weekly infusions have been associated to a reduced risk of VOD
as compared to single doses of higher concentrations [56]. VOD was
observed in 11% of patients treated with frontline mini-Hyper-CVD
and InO, mostly in non-transplanted patients in CR and ongoing
consolidation chemotherapy [60].
Epratuzumab: Epratuzumab is a humanized monoclonal
antibody targeting CD22 with limited activity as single agent. The
combination of epratuzumab and reinduction chemotherapy in 114
pediatric patients with early bone marrow relapse did not improve
the CR rate when compared to historical data obtained with the same
chemotherapy regimen (65% vs. 68%, respectively); however, a trend
towards improvement in MRD response with a more intensified
schedule of epratuzumab administration (twice weekly) was noted
[64]. A randomized phase 3 trial comparing standard chemotherapy
with or without epratuzumab in children with relapsed B-ALL is
ongoing.
In adults, epratuzumab was administered with a salvage
chemotherapy consisting of clofarabine and cytarabine in 31 R/R
patients. The overall response rate (CR/CRi) was 52%, significantly
higher than 17% obtained with the same regimen in the historical
cohort, but median OS was only 5 months [65]. To ameliorate
these results, epratuzumab was either coniugated to a radionuclide
(90Y-epratuzumab tetraxetan) or linked to a topoisomerase I
inhibitor (epratuzumab-SN-38). In a phase 1 study, 17 patients were
treated with 90Y-epratuzumab and 3 of them achieved CR [66].
Other clinical studies are ongoing with both agents.
Moxetumomab pasudotox (Ha22): Moxetumomab pasudotox
(MP) is a monoclonal anti-CD22 antibody fused to a 38-kDa
truncated fragment of the Pseudomonas aeruginosa exotoxin A. A
phase 1 study was conducted with a similar compound (known as
BL22) in pediatric patients, demonstrating the decrease of leukemic
blasts in 16 out of 23 B-ALL patients, but not CR [67]. MP was
administered to 21 children with R/R B-ALL every other day for 6
doses every 3 weeks: of 17 evaluable patients, 24% achieved CR, 6%
had partial response, and 47% had hematologic improvement for an
overall activity rate of 70% [68]. In adults, MP was administered every
other day for 6 doses (30 to 50 μg/kg) in 16 patients with R/R B-ALL,
including patients previously treated with InO and allogeneic SCT.
One patient with several prior treatments obtained CR, but no other
responses according to standard criteria were observed. AEs included
capillary leak syndrome, edema and elevation of liver enzymes [69].
Anti-CD52 monoclonal antibodies
CD52 is expressed in nearly all normal and malignant lymphoid
cells, including both B- and T-lymphocytes, making it the less specific
target for the immunological treatment of B-ALL.
Alemtuzumab: Alemtuzumab is a classic naked antibody
targeting CD52 and inducing cell lysis through ADCC. In a pediatric
study on R/R B-ALL (n=13), single agent alemtuzumab determined
only one CR and the authors concluded that further studies with this
compound were not justified [70]. The CALGB group tested the role
of alemtuzumab in 24 newly diagnosed CD52-positive ALL patients
as consolidation treatment after four post-remission chemotherapy
courses. Alemtuzumab was administered 3 times a week up to
a maximum dose of 30 mg. The median OS was 55 months, and 8
out of 11 patients with serial MRD measurements had at least 1-log
reduction in MRD [71]. In a smaller cohort of 12 adult patients with
R/R ALL alemtuzumab determined only transient responses [72].
Alemtuzumab was associated in all studies with significant toxicities,
including severe invasive fungal and CMV infections.
Chimeric Antigen Receptor (CAR) T-Cells
The concept of CAR modified T-cells was introduced more
than 20 years ago [73]. The aim of this approach was to induce
autologous T cells to identify and destroy malignant cells through the
interaction with tumor-specific antigens. Tipically, CAR molecules
are composed by an extracellular antigen-binding domain linked to a
cytosolic signalling domain, usually the ζ chain of the T-cell Receptor
complex, through a transmembrane domain. CARs recognize the
targeted surface antigen in a major histocompatibility complex
(MHC)-independent manner, so their function is not influenced by
the patient haplotype. First experiences with CARs reported poor
efficacy and persistance of engineered T cells, with many cases of graft
failure. This event has been attributed to the absence of intracellular
co-stimulatory domains (CD28 or 4-1BB), which have been added
starting from the second generation of CARs. Presently, “third
generation” CARs incorporate two co-stimulatory domains (i.e.
CD27, CD28, OX40/CD134 or 4-1BB/CD137) to favour engraftment
and improve T-cell proliferation, functions and persistence in the
host. [74].
Autologous T-cells are collected from the patient and CARs are
inserted in vitro by a vector capable of being integrated inside the
host cell genome [75]. Many ongoing clinical trials use retroviral
or lentiviral vectors, with some technical differences: in particular,
lentiviral vectors may transduce quiescent cells, while retrovirus
need cells in mitosis. A non-viral system (so called “sleeping beauty”)
consists in transducing T cells with the gene of interest through the
use of transposase and DNA plasmid [76]. However, despite inital
concerns about the oncogenic potential of viral vectors, there is no
evidence so far of clonal processes in patients treated with CARs,
even if modified T-cells may persist in the host for many years after
transfer [77]. Before reinfusion, autologous modified CAR-T cells
have to be expanded ex vivo to reach at least a 1-3 x 106 cells/kg dose.
CD19 CAR-T cells in relapsed/refractory patients
CD19-targeting CAR T-cells were mostly studied and displayed
significant activity in patients with refractory or relapsed B-cell clonal
diseases. Table IV summarizes the evidence of efficacy and relevant
CAR-T treatment-related emergent AEs.
In a phase 1 trial conducted at the University of Pennsylvania,
30 pediatric (n=25) and adult (n=5) patients with relapsed/refractory
ALL were treated with lympho-depleting chemotherapy followed
by infusion of autologous T cells engineered with a CD19-directed
CAR (CTL019). Twenty-seven patients (90%) obtained CR 1 month
after the infusion, with 6-month EFS and OS rates of 63% and
78%, respectively [78]. Another phase 1 dose-escalation trial was
conducted at the National Cancer Institute (NCI) on 21 patients with
R/R ALL or NHL. Age ranged from 1 to 30 years and all patients
received fludarabine and cyclophosphamide before CD19-CAR T cell
infusion. CR rate was 66% and MRD-negative complete response was
observed in 60% of B-ALL patients (12 out of 20). OS was 51.6%, with
a median follow up of 10 months [79]. Similar data were reported
by Davila et al. [80] in 24 R/R B-ALL patients treated with salvage
chemotherapy followed by infusion of 19-28z CAR T cells. CR was
documented in 20 out of 22 evaluable patients (91%) and MRDnegative
remission was observed in 80% of them. In a recent phase
1/2 trial, CD8+ and CD4+ autologous T cells were separately modified
to express a CD19-directed CAR, and infused in a defined CD4+:CD8+
ratio. CR was achieved by all treated patients, while MRD complete
response was observed in 27 out of 29 evaluable patients (93%). T-cell
mediated anti-CAR immune response was identified in some patients
as a mechanism of reduced CAR T-cell persistence, and increased
relapse risk; addition of fludarabine to lympho-depleting regimen
improved CAR T-cell persistence and DFS [81]. Emerging evidence
from all these studies suggests that duration of response correlates
with the proliferation degree of transferred CAR-T cells in the
recipient and their persistence in vivo. Factors determining CAR-T
cell expansion and persistence are not well defined, mainly because
of differences in CAR-T cell manifacturing, doses administered to
patients, and lympho-depleting chemotherapy. Relapses are most
likely due to short persistence of engineered T-cells, but CD19-
negative relapses have also been observed, as occurring in patients
treated with blinatumomab. Regardless the significant percentage
of relapse, approximately 50% of patients treated with CAR-T cells
maintained CR and underwent allogeneic HSCT.
CD19 CAR-T cells safety
The most common and serious toxicity described after CARmodified
T-cell therapy is the cytokine release syndrome (CRS),
which has been observed nearly in all patients a few hours or days
after infusion and correlates with tumor load. CRS is an inflammatory
process due to excessive T cell proliferation with consequent release
of cytokines. Generally, this may cause a number of symptoms
ranging from mild to severe, including fever, myalgia, hypotension,
nausea and vomiting or even multi-organ failure syndrome. Lifethreatening
CRS have been observed in patients with high tumour
load. In these cases the inhibitor of the IL-6 pathway tolicizumab
has been successfully employed. Corticosteroids represent a
second line-treatment, as they could prevent CAR T-cells function.
Another treatment-related side effect is neurotoxicity, occurring in
around 40% of patients: similarly to blinatumomab, neurotoxicity
is often self-limited and can include confusion, aphasia, seizure or
encephalopathy. Persistent B-cell aplasia is constant and due to the
profound depletion of normal B lymphocytes, thus requiring longterm
prophylactic administration of intravenous immunoglobulins.
No GvHD has been described so far in patients treated with CAR-T
cells because of relapse after prior allogeneic HSCT.
Table 2
Table 2
CR/CRh: Complete Remission/Complete Remission with Incomplete Hematological Recovery; MRD: Minimal Residual Disease; RFS: Relapse-Free Survival; R/R: Relapsed/Refractory; SOC chemo: Standard of Care Chemotherapy; n.r.: Not Reported; *: MRD-negative state among CR/CRh responders
Table 3
Table 4
Conclusion and Future Perspectives
Novel immunotherapy represented a major improvement in
the treatment of BCP ALL and determined previously unmet high
rates of CR and MRD complete response also in heavily pretreated
patients. Three agents are particularly promising: the anti-CD19/
CD3 BiTE antibody blinatumomab, the anti-CD22 chalicheamicinconjugated
antibody inotuzumab ozogamicin, and anti-CD19
CAR-T cells. All these treatments were proved effective in R/R
patients with particularly unfavourable characteristics (i.e. primary
refractory, early relapse, and relapse after HSCT) and blinatumomab
was effective also in determining complete MRD clearance in the
majority of patients with high MRD burden. However, the median
duration of response and OS obtained in these conditions is far from
optimal. The mechanisms of resistance to these agents are not fully
elucidated. Emergence of CD19-negative clones and extramedullary
relapse in immunological “sanctuaries” were observed during the
first studies with blinatumomab and CAR T-cells and postulated as
the main causes of failure; nevertheless, longer follow-up and many
more treated patients made clear that most of relapse cases are driven
by CD19+ cells and occur also in the bone marrow. Considering
the rapidity of relapse also in patients with deep levels of molecular
response, it was hypothesized that blinatumomab might neither affect
the leukemic stem cell compartment nor prevent the emergence of
genetically unstable subclones [82]. Also durability of response after
CAR-T cells remains a major concern, and phase 2 studies should
determine which manifacturing characteristics correlate with CAR-T
cells persistence and EFS.
The main question to be addressed is the role of allogeneic HSCT
in the immunotherapy era. To date, HSCT were proposed to all
eligible patients, as immunotherapy was seen primarily as a bridge
to transplant: however, no difference in OS were observed in R/R
patients when censoring for HSCT both in blinatumomab [32] [35]
and InO [56] trials, because the outcome of HSCT was influenced
by high post-SCT mortality. One may speculate that anticipating
immunotherapy during induction or early consolidation, i.e. before
the occurrence of resistant subclone selection and in presence of
relatively preserved immunocompetence, would lead to a better
outcome, thus eventually representing a valid alternative to HSCT.
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