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

444s Leukemia, Myelodysplasia, and Transplantation
6612 General Poster Session (Board #23G), Mon, 1:15 PM-5:15 PM
High frequency of BCR-ABL oncogene in pediatric acute lymphoblastic
leukemia (ALL) patients as revealed by RT-PCR and interphase FISH:
Association with disease biology and treatment outcome. Presenting
Author: Zafar Iqbal, Molecular Genetic Pathology Unit, Department of
Pathology, College of Medicine and KKUH, King Saud University, Riyadh,
Saudi Arabia; and Haematology, Oncology and Pharmacogenetic Engineering
Sciences (HOPES) Group, HSRL, Zoology Department, University of the
Punjab, Lahore, Pakistan
Background: ALL is a complex genetic disease involving many fusion
oncogenes (FGs) 1 frequency of which can vary in different ethnic groups2,3 thus having implication in differential diagnosis, prognosis and treatment.
Methods: We studied FGs in 101 pediatric ALL patients using RT-PCR1 at
Day 0, Day 15 and Day 29 and Interphase FISH, and their association with
clinical features and treatment outcome. Results: Five most common FGs
i.e. BCRABL (t 22; 9), TCF3-PBX1 (t 1; 19), ETV6-RUNX1 (t 12; 21),
MLL-AF4 (t 4; 11) and SIL-TAL1 (del 1p32) were found in 88.1%
(89/101) patients. Frequency of BCR-ABL was 44.5% (45/101). Patients
with BCR-ABL had significantly lower survival (43.733 weeks �4.241) as
compared to others except MLL-AF4 and significantly higher TLC count.
Overall survival was lower (52.2�3.75) than the patients with ETV6-RUN X
1 (65.2� 9.9) which may be due to overall high frequency of poor
prognostic FGs (71%) as compared to ETV6-RUNX 1 (17.1%) (p�0.01).
Conclusions: This is the first study from Pakistan correlating molecular
markers, disease biology and treatment response. It is the highest reported
frequency of BCR-ABL in pediatric ALL and was associated with disease
biology and survival. Some authors have reported BCR-ABL frequency
higher than in West2,4,5 while others reported 45% frequency of ETV6-
RUNX16 . These and our data reflect strong interplay of genetic and
environmental factors in biology of pediatric ALL and its correlation with
disease biology and treatment2,3 . Our data indicates immediate need for
large clinical trials of imatinib, dasatinib and nilotinib in paediatric ALL
treatment in our ethnic group. This study will lead to unravel the
mechanisms of BCR-ABL Leukemogenesis and to find population-specific
biomarkers and drug targets. References: 1) van Dongen JJ, et al.,
Leukemia. 1999 Dec; 13(12):1901-28. 2) Iqbal Z, et al. J Pediatr
Hematol Oncol. 2007 Aug; 29(8):585. 3) Ariffin H, et al. J Pediatr Hematol
Oncol. 2007 Jan; 29(1):27-31. 4) Ramos C, et al. 2011 Sep; 139(9):1135-
42. 5) Artigas A CG, et al. Rev Med Chil. 2006 Nov; 134(11):1367-76. 6)
Karrman K, et al. Br J Haematol. 2006 Nov; 135(3):352-4.
6614 General Poster Session (Board #24A), Mon, 1:15 PM-5:15 PM
CDKN2A-deletion to predict relapse in adult B-cell acute lymphoblastic
leukemia (B-ALL). Presenting Author: Preet Paul Singh, Mayo Clinic,
Rochester, MN
Background: CDKN2A locus on chromosome 9p21 is implicated in altered
molecular pathways leading to leukemogenesis as a tumor suppressor by
inhibiting the proliferative kinases CDK4/CDK6 and blocking the cell-cycle
division during G1/S phase. Deletion of CDKN2A locus is frequently seen in
ALL, although prognostic significance remains unclear. Methods: Retrospective
chart review at Mayo Clinic between 8/2005-11/2011 was performed
on adult B-ALL patients (pts) who underwent fluorescent in situ hybridization
(FISH) studies at diagnosis. Survival estimate was calculated using
Kaplan-Meier statistics. Event-free survival (EFS) was defined as time
between diagnosis and induction failure, relapse, or death, while overall
survival (OS) as time between diagnosis and death Results: Out of 27 pts
who had FISH studies for CDKN2A, 15 (56%) pts had CDKN2A deletions
(8 homozygous/7 hemizygous), while 12 (44%) pts had diploid cytogenetics
(none had abnormalities of MLL, bcr/abl fusion or CDKN2A deletion on
FISH). There was no significant difference in median age, gender, WBC,
hemoglobin, platelet count, LDH or complete remission (CR) rate (p�0.924)
between the two groups. CDKN2A-deleted pts had higher circulating blasts
(34% vs 16%, p�0.017). Of 13 CDKN2A-deleted pts, chromosome 9p
was intact in 9 (69%) pts using routine cytogenetics. In the CDKN2Adeleted
group, allogeneic stem cell transplant (ASCT) was performed in 7
(47%) pts at first CR and 1 at second CR. Four of 15 (27%) CDKN2Adeleted
pts also had bcr/abl fusion. Five-year EFS was poorer in CDKN2Adeleted
pts compared to normal FISH group (22% vs 60%, p�0.042),
while 5-year OS was 72% vs 60% (p�0.308), respectively. Excluding the 4
bcr/abl fusion pts, 5-year EFS was still statistically significant (p�0.008).
In the CDKN2A deleted group, both 5-yr EFS (80% vs 0%, p�0.006) and
OS (100% vs 42%, p�0.016) were significantly superior in pts who
received ASCT. Conclusions: CDKN2A deletions predict earlier relapse in
pts with B-ALL. Majority of 9p abnormalities were only found by FISH
testing and missed by conventional cytogenetics. In CDKN2A deleted pts,
ASCT gave overall survival advantage. Further investigation through larger
cohorts of pts is needed to validate these findings.
6613 General Poster Session (Board #23H), Mon, 1:15 PM-5:15 PM
Safety and efficacy of dose escalated liposomal amphotericin B in adult
leukemia patients with refractory invasive fungal infections: A single
institution report. Presenting Author: Sherry Mathew, Memorial Sloan-
Kettering Cancer Center, New York, NY
Background: Leukemia patients are at risk for invasive fungal infections(IFI).
Empiric therapy of suspected IFI is begun due to fever despite
appropriate antibiotics during neutropenia or infiltrates on chest CT.
Liposomal amphotericin B (L-AmB) is used for empiric anti-fungal therapy
at 3-5 mg/kg. Data is lacking on the efficacy of L-AmB dose escalation in
patients with CT progression and clinical decline. Methods: Patients who
received 10 mg/kg of L-AmB from 2002-11. They were required to be �18
years old and escalated from 5 to 10 mg/kg L-Amb for at least 7 doses.
Patient information was collected from pharmacy and medical records.
Successful treatment was defined as resolution of fever at least 1 week after
high dose L-AmB and/or improvement or stability on chest CT. Renal and
hepatic toxicity was assessed. Clinical remission was defined as recovery of
a normal neutrophil count. IRB approval was obtained for this study.
Results: 58 patients were evaluated. At the time of presumed or probable
IFI, 19 had completed induction therapy, 5 had received supportive
therapy, and 34 had received 2 or more cycles of therapy. High dose L-AmB
was begun for CT findings and fever, CT findings only, and fever only in 14,
26, and 17 patients, respectively. Patients received a median of 15 doses
of high dose L-AmB, and all received concomitant therapy with an
echinocandin except two: 1 received nothing and 1 received voriconazole.
Treatment success was seen in 28 (48%) patients. Twenty-nine (50%)
patients were alive at 12 weeks and 10 (17%) patients proceded to BMT.
Only 11 (39%) of the responding patients achieved a clinical remission. All
patients received IV hydration and electrolyte repletion. Six patients had a
grade 2 increase in serum creatinine and 10 patients developed grade 2 or
3 hepatic toxicity. There were no grade 4 adverse events. Conclusions:
Although it has been reported that L-AmB at 10mg/kg was inferior to 3
mg/kg in untreated patients, our study supports a safe dose escalation
strategy to 10mg/kg in treating progressive presumed or probable IFI and
should be considered a clinical alternative for these high risk patients.
6615 General Poster Session (Board #24B), Mon, 1:15 PM-5:15 PM
Time to ATRA in suspected newly diagnosed acute promyelocytic leukemia
and association with early death rate at a non-cancer center institution: Are
we meeting the target? Presenting Author: Gulam Abbas Manji, Albany
Medical Center, Albany, NY
Background: ATRA administration in suspected APL patients (sAPL) is
thought to impact early death rate (EDR) (Tallman and Manji, Blood Cells
Mol Dis. 2011). Delay in ATRA therapy at specialized centers was
associated with EDR (Altman et al Blood 2011). EDR within this study was
significantly lower compared to the SEER database (12% vs 17.3%) and
hence may not reflect overall delay in ATRA therapy. We determined time to
ATRA therapy in sAPL, and fraction of sAPL that did not have disease.
Methods: Retrospective analysis of patients that received ATRA for newly
diagnosed s APL between 01/01/98-12/31/11 at Albany Medical Center.
Time to hematologist evaluation, ATRA ordered and administered, and
mortality data was collected from cancer registry, medical record, and
chemo-pharmacy database. Results: A total of 39 patients with newly
diagnosed sAPL were administered ATRA (46% male, mean age 50y). APL
diagnosis: 29/39 (75%) true APL (APL); 9/10 ATRA-treated non-APL
(A-nAPL); and one patient for whom cytogenetic data unavailable. EDR
amongst APL was 5/29 (17%) compared to 2/9 (22%) within A-nAPL. Time
variables were compared between APL patients that died early (�30d) to
those that survived 30 days, and included: time to hematologist response
(0.9d vs. 0.4d); time to ATRA ordered (2.9d vs. 2.0d); time to ATRA
administered (3.4d v. 2.2d); and time elapsed between hematologist
response to ATRA administered (2.5d v. 1.9d), respectively. Cryoprecipitate
was administered to 1/5 (20%) patients who expired within 30d
compared to 10/23 (43%) who survived. Overall mortality for APL was 9/29
(31%) compared to 4/9 (44%) for A-nAPL group. Compared to recent
reports, time to ATRA administration in our institution was later (2.0d vs.
2.4d). Conclusions: Our data indicate that APL patients who survived 30d
received ATRA early. EDR at our institution is comparable to that reported
by SEER database and may be attributed to delay in ATRA administration.
Higher fraction of patients that survived 30d received cryoprecipitate.
Hence aggressive blood product support may contribute to improved
survival. Timing at which these products were administered is currently
being evaluated.
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