Annual Meeting Proceedings Part 1 - American Society of Clinical ...

618s Pediatric Oncology
9548 General Poster Session (Board #40C), Sun, 8:00 AM-12:00 PM
Safety and biological activity of the FLT3 inhibitor lestaurtinib in infant
MLL-rearranged (MLL-r) ALL: Children’s Oncology Group protocol
AALL0631. Presenting Author: Di Sun, Oncology and Pediatrics, Johns
Hopkins University School of Medicine, Baltimore, MD
Background: MLL-r infant ALL overexpresses activated FLT3. Lestaurtinib
potentiates chemotherapy(chemo)-induced cytotoxicity in MLL-r ALL.
AALL0631 therapy is stratified based on age and MLL status: high risk
(HR) �90 days, MLL-r; intermediate risk (IR) � 90 days, MLL-r; standard
risk any age, not MLL-r. IR and HR patients (pts) get intensive chemo and
are eligible for lestaurtinib. A safety/activity (S/A) phase to determine a safe
and biologically active dose of lestaurtinib is followed by an efficacy phase
randomizing MLL-r patients to chemo �/- lestaurtinib. The S/A phase
proceeds independently for IR & HR pts, as optimal lestaurtinib dosing may
differ between neonates and older infants. We previously reported successful
completion of the S/A phase for IR pts; here, we report results of the S/A
phase for HR pts. Methods: Lestaurtinib-related dose limiting toxicities
(DLTs) were defined as grade � 3 non-heme toxicities excluding those
expected with chemo alone (e.g., F&N/infection); a dose of lestaurtinib was
“safe” if 0 or 1 DLTs were seen in 5 evaluable pts. FLT3 inhibition was
assessed using a plasma inhibitory activity (PIA) assay that measures %
inhibition of phospho-FLT3 at 5 trough time points relative to pretreatment
baseline. A dose of lestaurtinib was “biologically active” if PIA
was � 90% for the majority (�3 of 5) of troughs in at least 3 of 5 pts.
Results: 11 eligible HR pts received lestaurtinib, 6 at dose level 1 (DL1, 3.5
mg/kg/day) and 5 at DL2 (4.25 mg/kg/day). There were no DLTs in 5
evaluable pts at DL1. The inevaluable pt discontinued lestaurtinib due to
parental refusal, not toxicity. There was 1 DLT in 5 evaluable pts at DL2.
The DLT was grade 4 intestinal perforation secondary to severe typhlitis
during neutropenia following reinduction, possibly related to lestaurtinib.
The pt was taken off protocol and chemo and died of progressive disease.
By PIA assay, 2 of 5 pts treated at DL1, and 4 of 5 at DL2 demonstrated
FLT3 inhibitory biologic activity. Conclusions: DL2 is safe and biologically
active in HR pts. The efficacy phase of AALL0631 is expanding such that
HR pts will join IR pts in being randomized (1:1) post-induction to chemo
�/- lestaurtinib at DL2.
9550 General Poster Session (Board #40E), Sun, 8:00 AM-12:00 PM
Diminished asparaginase turnover due to a germ-line mutation in cathepsin
B. Presenting Author: Dunja Maroeslea W.M. Te Loo, Radboud University
Medical Centre, Nijmegen, Netherlands
Background: ASNase is a key component of multi-agent chemotherapy
protocols used in the treatment of pediatric as well as adult acute
lymphoblastic leukemia (ALL). Patients that are treated according to fixed
shedules show a strong inter individual variation in serum ASNase levels.
While underexposure may compromise therapeutic benefits, strongly elevated
serum levels may lead to serious adverse effects. In at least 10% of
the patients the desired ASNase levels are either not reached or exceeded.
Therefore our understanding of ASNase dynamics in vivo needs to be
improved. Here we describe the identification of a novel mutation in the
gene encoding Cathepsin B to diminished ASNase turnover in a pediatric
patient with ALL. Methods: Sequencing, biochemical experiments and
immunofluorescence. Results: A 3-year-old girl diagnosed with ALL experienced
serious toxicity in the form of hyperammonemic encephalopathy
during treatment with ASNase derived from Erwinia chrysantemi. Pharmacokinetic
data showed a strongly delayed clearance of the ASNase, which
with the standard treatment protocol resulted in extremely high serum
ASNase levels. Plasmapheresis was performed and dosage frequencies
were adjusted to improve the clinical status of the patient. No underlying
metabolic disorder could be diagnosed. Based on a previous report
describing the role of proteases in degradation of ASNase in vitro, we
hypothesized that the cysteine protease Cathepsin B might be implicated in
the strongly reduced clearance of ASNase in this patient. Sequencing of the
open reading frame of the Cathepsin B gene (CTSB) revealed a single codon
deletion in the germline of the patient, affecting a lysine residue in the
carboxy terminus of the protein. Immunofluorescence and biochemical
experiments show that this single amino acid deletion leads to a protein
product that is retained in the endoplasmic reticulum and is inefficiently
processed. Conclusions: ASNase degradation assays show that the mutant
Cathepsin B has lost its ability to efficiently degrade ASNase which could
explain the high levels of ASNase as observed in our patient.Together,
these findings suggest that variations in Cathepsin B activity may influence
serum ASNase levels in the patients.
9549 General Poster Session (Board #40D), Sun, 8:00 AM-12:00 PM
Serial assessment of regulatory T cells (Tregs) in pediatric AML: A
prospective study. Presenting Author: Anuj Kumar Bansal, All India
Institute of Medical Sciences, New Delhi, India
Background: Data of Tregs in pediatric AML is lacking. The study objectives
were determining Tregs in pediatric AML at diagnosis and follow up; and
correlating with outcome. Methods: From Nov 2010-May 2011, 30 consecutive
AML patients � 18 years were prospectively enrolled with 6 healthy
controls. All patients received daunorubicin / cytarabine induction and 3
courses of cytarabine. Tregs (CD4�CD25�FoxP3�) were assessed at
diagnosis, post-induction, post-consolidation, 3 and 6 months follow up
and relapse. Results: 30 cases with median age 9.5 years; male/female ratio
14:16 had significantly higher baseline Tregs than healthy controls
(12.36�4.65% vs 3.16�1.49%; p�0.0001). Patients with high Tregs
frequency were females (p�0.044), WBC�50,000/mm3 (p�0.023), hypoalbuminemia
(p�0.002), absence of lymphadenopathy (p�0.04) and
linear correlation with peripheral blood blast% (r�0.55, p�0.0014). CR
rate was 83.3% (25/30); EFS 38% and OS 73% at 14 months follow up.
When Tregs were categorized as high and low based on median value, CR
rate (86.6% vs 80%, p�NS), EFS [17% vs 60%, HR 1.46 (0.51-4.14)
p�0.46] and OS (66% vs 80%, HR 0.58 (0.13-2.44) p�0.45) were not
different. Amongst those who achieved CR, there were 7/13 relapses in
those with high Tregs versus 3/12 in those with low Tregs (p�0.226).Tregs
reduced post-induction (12.1�4.6 vs 6.32�2.8, p�0.000) from baseline.
Using generalized estimating equation regression model, average
Tregs reduction from post-induction till 3 month follow up was 0.785
units/visit (p�0.005) in those with continuous CR(n�15) and 1.25
units/visit (p�0.001) in those whom relapsed (n�10). Difference between
these two groups was not significant. Tregs significantly increased at
relapse as compared to post consolidation value (15.3�5.2 vs 4.5�1.9,
p�0.003). Conclusions: This first study in pediatric AML demonstrates that
Tregs is increased at diagnosis and is significantly associated with females,
high WBC count, hypooalbuminemia, absence of lymphadenopathy and
high peripheral blood blast%. Tregs significantly reduced post-induction on
follow up; however, it increased at relapse. Baseline Tregs did not predict
CR, EFS, or OS. However, there were more relapses in those with high
baseline Tregs.
9551 General Poster Session (Board #40F), Sun, 8:00 AM-12:00 PM
Serial assessment of humoral immunity in pediatric AML: A prospective
study. Presenting Author: Sameer Bakhshi, Dr. B.R. Ambedkar Institute
Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi,
India
Background: Humoral immunity has been evaluated in pediatric ALL; data
in pediatric AML is lacking. The objectives of this study were to assess
humoral immunity on follow-up in pediatric AML patients. Methods: From
April 2010-May 2011, 45 consecutive AML patients 1-18 years old were
prospectively enrolled with 7 healthy controls. Immunoglobulin (Ig) levels
in 45 patients and B-lymphocytes (CD19�) in 29 patients were assessed at
diagnosis, post-induction, post-consolidation, 3 and 6 months follow-up
and relapse. Results: At diagnosis, Ig levels were higher in patients as
compared to healthy controls (IgG, p�0.041; IgA, p�0.07; IgM, p�0.16)
while B-cells were lower (p�0.001). Patients with gum hypertrophy had
low Ig levels (IgG, p�0.007; IgA, p�0.003; IgM, p�0.06). CR rate was
84.4% (38/45); EFS 40% and OS 58% at 20 months follow-up. Postinduction,
there was reduction in IgM (p�0.001) and IgA (p�0.048) levels
and increase in B cells (p�0.001). Using generalized estimating equation
regression model, average reduction from post-induction till 3 month
follow-up was 36.9 units/visit (IgG); 10.3 units/visit (IgA); 0.32 units/visit
(IgM) in those with continuous CR (group-1, n�24) and 91 units/visit
(IgG); 8.9 units/visit (IgA); 1.5 units/visit (IgM) in those who relapsed
(group-2, n�14). Difference between these two groups was significant for
IgA (p�0.017). There was increase in IgG (p�0.52) and IgA levels (0.21)
at relapse when compared with post-consolidation values. B-cells had an
average increase of 3.6 units/visit (p�0.012) in group 1 and decrease of
0.58 units/visit (p�0.82) in group 2; (group-1 vs group-2, p�0.10). There
was no significant correlation of baseline Ig and B cells with CR rate, EFS
and OS. Conclusions: This is the first study to evaluate humoral immunity
serially in pediatric AML. AML patients with gum hypertrophy have low IgG
and IgA at diagnosis. On serial monitoring, B cells show an increase in
patients who are in continuous CR while those who relapse tend to show a
reduction on follow-up. Further, on follow-up, although all Ig decrease, but
the reduction in IgA is significantly lower in patients who relapse suggesting
their possible role in disease biology.
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