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

9504 Oral Abstract Session, Sat, 1:15 PM-4:15 PM
Cardioprotection and safety of dexrazoxane (DRZ) in children treated for
newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL) or advanced
stage lymphoblastic leukemia (T-LL). Presenting Author: Barbara Asselin,
University of Rochester, Rochester, NY
Background: POG 9404 evaluated the efficacy of DRZ as a cardioprotectant
and its side effects in children receiving doxorubicin (DOX) as part of
chemotherapy for T-ALL/T-LL. Methods: Between 6/1996 and 9/2001, 537
T-ALL/T-LL patients were treated with multi-agent chemotherapy that
included 12 DOX doses of 30 mg/m2 . Patients were randomized at
diagnosis to treatment with or without DRZ (300 mg/m2 IV immediately
prior to each DOX dose). Cardiac effects were assessed by serial echocardiograph
measurements of left ventricular (LV) function (fractional shortening)
and structure (end-diastolic dimension, wall thickness, and mass). Adverse
events, grades 3-5 were recorded using CTCAE version 2.0. Results:
Five-year EFS was similar for the DRZ (0.77�0.03%) and no-DRZ
(0.76�0.03%) groups (p�0.9). Acute cardiac toxicity occurred in 1
patient (arrhythmia) on DRZ and 4 patients treated without DRZ (1arrhythmia,
3-decreased LV fractional shortening). At each of the three
time-points post-baseline (end-induction, after the last DOX dose and two
years post study entry) LV dimensions were larger from baseline for patients
who did not receive DRZ. In univariate analyses, change in LV end-diastolic
dimension from baseline was the only variable that was significantly
different between DRZ and no-DRZ arms. This was true at each of the three
time points (p�0.005-0.02). The frequencies of grade 3 or 4 toxicity
(hematologic, infection, CNS events, mucositis) or death were similar in
groups with or without DRZ (p�0.24). There were 13 second malignancies,
10 patients had received DRZ and 3 had not (p�0.07). Conclusions: Our LV
dimension measurements suggest that DRZ may protect against the early
LV remodeling and enlargement that is seen with DOX cardiotoxicity.
Addition of DRZ did not interfere with the anti-tumor efficacy of this
DOX-containing, multi-agent regimen, and there was no significant increase
in toxicities. An increased rate of second malignancies with DRZ did
not reach conventional levels of statistical significance. The study was not
powered to assess second malignancy rates and this trend is of unknown
clinical significance.
9506 Oral Abstract Session, Sat, 1:15 PM-4:15 PM
In vivo monitoring of JAK/STAT and PI3K/mTOR signal transduction
inhibition in pediatric CRLF2-rearranged acute lymphoblastic leukemia
(ALL). Presenting Author: Sarah Kathleen Tasian, The Children’s Hospital
of Philadelphia, Philadelphia, PA
Background: Therapy intensification for children with B-precursor ALL with
high-risk genetic lesions has improved relapse-free survival. CRLF2 rearrangements
and JAK2 and IL7RA mutations occur in 10-15% of adult and
pediatric ALL patients, most of whom relapse. We and others identified
aberrant kinase signatures and perturbed JAK/STAT and PI3K/mTOR signal
transduction via in vitro studies of CRLF2-rearranged (CRLF2r) ALLs,
suggesting the therapeutic relevance of signal transduction inhibitors
(STIs). Our creation of CRLF2r ALL xenograft models has enabled rapid
preclinical testing of STIs and measurement of in vivo target inhibition. We
hypothesized that inhibition of JAK/STAT and PI3K/mTOR phosphosignaling
correlates with therapeutic responses in these models. Methods:
NOD/SCID/�c-null (NSG) mice well-engrafted with pediatric ALL samples
were treated with the JAK inhibitor ruxolitinib, the mTOR inhibitor
sirolimus, or vehicle for 72 hours (for signaling response) or 4 weeks (for
therapeutic response). Splenocytes were briefly stimulated ex vivo with
thymic stromal lymphopoietin (ligand for CRLF2) and stained with humanspecific
surface and intracellular phosphoantibodies for multi-parameter
phosphoflow cytometry analysis. Results: Ruxolitinib-induced inhibition of
phospho (p)-JAK2 and pSTAT5 was most pronounced in non-CRLF2r ALLs
with novel JAK2-activating BCR-JAK2 and IL7RA/LNK mutations. Sirolimus
potently inhibited pS6 and other PI3K/mTOR pathway phosphoproteins
in the CRLF2r r ALLs. PSTAT5 and pS6 inhibition correlated with
longer-term ruxolitinib- and sirolimus-induced decreases in ALL cell
burden, demonstrating therapeutic responses to STIs. Conclusions: Ruxolitinib
inhibited JAK/STAT phosphosignaling and markedly decreased
leukemic burden in the JAK2-activating BCR-JAK2 and IL7RA/LNK mutant
ALL xenografts. Sirolimus potently inhibited PI3K/mTOR (as well as some
JAK/STAT) phosphosignaling and had greater therapeutic efficacy than
ruxolitinib in the CRLF2r ALLs. The safety of ruxolitinib and of temsirolimus
with cytotoxic chemotherapy are currently being established in Children’s
Oncology Group Phase I trials.
Pediatric Oncology
9505 Oral Abstract Session, Sat, 1:15 PM-4:15 PM
Efficacy of the Children’s Oncology Group (COG) long-term followup
(LTFU) guidelines in reducing risk of congestive heart failure
(CHF) in childhood cancer survivors (CCS). Presenting Author: F.
Lennie Wong, City of Hope, Duarte, CA
Background: CCS are at risk for left ventricular dysfunction (LVD) and
subsequent CHF due to exposure to anthracyclines and chest radiation
(RT). COG LTFU guidelines recommend screening for LVD using echocardiograms
(ECHOs) every 1-5y depending on anthracycline dose, RT, and
age at cancer diagnosis. The relevance and cost-effectiveness of these
consensus-based guidelines are unknown. Methods: Life expectancy and
age at onset of CHF were projected in a simulated cohort (�1 million) of
CCS undergoing screening ECHO per COG guidelines. Intervention for LVD
was modeled to reduce annual CHF risk by 30%. Quality-adjusted life-years
(QALYs) and lifetime costs with and without ECHO screening were
calculated. Non-CHF mortality was estimated from the Childhood Cancer
Survivor Study and US population rates. Costs and QOL adjustments were
obtained from the Healthcare Cost and Utilization Project and medical
literature. Screening was considered cost-effective if it resulted in a �6
month delay in onset of CHF and �$50,000/QALY gained. Results:
Recommended screening strategies (Table) were cost-effective in: i) CCS
exposed to �300mg/m² of anthracycline regardless of RT or age; and ii)
CCS diagnosed at age 1-4y, exposed to RT and �300mg/m² of anthracycline.
Screening was most cost-effective for CCS diagnosed at age 1-4y
exposed to RT � �300 mg/m² of anthracycline (1.4y delay in CHF onset;
$15,821/QALY gained). Screening as currently proposed was not costeffective
for other age/anthracycline/RT combinations. Conclusions: Recommended
ECHO screening strategies are cost-effective for all CCS exposed to
�300 mg/m² of anthracycline; screening was also cost-effective for those
1-4y at diagnosis, exposed to anthracycline �300 mg/m² � RT. Alternate
screening strategies are needed for CCS with other exposure conditions.
Age Dx
(years) RT
Anthracycline
dose
(mg/m²)
Recommended
ECHO
interval
(years)
Delay in
CHF onset age
(years)
607s
Cost / QALY
gained
(US$)
1-4 Yes �300 1 0.8 $49,750
�300 1 1.4 $15,821
No �100 5 0.3 $17,798
100-299 2 0.4 $29,415
�300 1 1.2 $25,065
>5 Yes �300 2 0.4 $36,874
�300 1 0.8 $28,093
No � 200 5 0.1 $50,750
200-299 2 0.2 $86,867
�300 1 0.7 $36,401
9507 Oral Abstract Session, Sat, 1:15 PM-4:15 PM
Relapse-specific mutations in cytosolic 5’-nucleotidase II in childhood
acute lymphoblastic leukemia. Presenting Author: Julia Meyer, New York
University Langone Medical Center, New York, NY
Background: Relapsed childhood acute lymphoblastic leukemia (ALL)
carries a very poor prognosis despite intensive retreatment that often
includes allogeneic stem cell transplantation, due to intrinsic drug resistance.
Novel therapeutic approaches are urgently needed and identification
of the biological pathways that mediate resistance might provide targets for
the effective prevention and treatment of relapsed ALL. However, the
spectrum of somatic mutations responsible for ALL relapse is not yet
known. Methods: We profiled the transcriptome of matched diagnosis and
relapse bone marrow specimens from 10 pediatric B lymphoblastic
leukemia patients using massively parallel sequencing technology (RNAseq)
to identify novel mutations specific at disease recurrence. Results:
Transcriptome sequencing identified 20 newly acquired novel nonsynonymous
mutations in 10 relapse specimens not present at initial
diagnosis. Two patients harbored relapsed specific mutations in the same
gene, NT5C2, which codes for the Cytosolic 5’-nucleotidase II protein at
different sites in the protein sequence. Mutations were validated as relapse
specific after Sanger resequencing of germline, diagnosis and relapse DNA.
RNA-seq coverage of each mutation was �100X, indicating that if a
relapsed clone were present at diagnosis it made up � 1% of the bulk
leukemia. Full exon sequencing of NT5C2 was completed in 61 additional
relapse specimens, identifying 5 additional mutations which were also
confirmed as relapse specific. Structural modeling of the relapseassociated
mutations in the encoded protein Cytosolic 5’-nucleotidase II
suggests alteration of enzyme subunit association/dissociation. Clinically,
patients who harbored NT5C2 mutations were more likely to relapse earlier
following initial diagnosis than those patients without mutations (p�0.03).
Conclusions: Mutations in NT5C2 are associated with the outgrowth of drug
resistant cells in childhood ALL.
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