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

6528 Poster Discussion Session (Board #20), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Effect of fludarabine, cytarabine, filgrastim, and gemtuzumab ozogamicin
(FLAG-GO) on relapse-free survival in patients with newly diagnosed
core-binding factor acute myelogenous leukemia. Presenting Author: Gautam
Borthakur, University of Texas M. D. Anderson Cancer Center,
Houston, TX
Background: Prior modulation with fludarabine increases cytarabinetriphosphate
(ara-CTP) accumulation and granulocyte-colony-stimulating
factor (G-CSF) increases the fludarabine-triphosphate (F-ara-ATP) levels in
leukemic blasts. Our front-line regimen of fludarabine, cytarabine and
filgrastim (FLAG) based on this rationale showed improved event-free
survival compared to anthracycline and cytarabine based regimens in
patients (pts) with core-binding factor acute myelogenous leukemia (CBF-
AML). Medical Research Council AML 15 trial reported survival benefit
from addition of gemtuzumab ozogamicin (GO) to chemotherapy regimens
in patients with favorable-risk cytogenetics AML. Methods: In a clinical trial
combining GO (3 mg/m2 IV) with FLAG (FLAG-GO) in newly diagnosed
CBF-AML, pts received GO on day 1 of induction and of post-remission
cycles 2 or 3 and 5 or 6 in addition to FLAG. FLAG regimen was comprised
of fludarabine 30 mg/m2 and cytarabine 2 gm/m2 IV daily (both for 5 days in
induction and 3-4 days in post-remission cycles) with filgrastim started on
day-1 and continued till neutrophil recovery. Pts who received one
non-FLAG-GO induction could enroll irrespective of their remission status.
Results: Fifty pts [30 with t(8;21) and 20 with Inv16] have been enrolled [5
of 50 (10%) were in remission at enrollment from prior induction]. Median
age is 48 years (range, 19-76), median WBC count 12.3 x106 /L (range,
1.3-97.2); 12 patients (24%) were �60 years of age and frequency of kit
mutation is 8%. Complete remission with or without platelet recovery
(CR/CRp) was achieved in 43/45 (96%) pts with 2 deaths in induction.
With 6 planned consolidations, the median number of consolidation
treatments received is 5 (range, 0-6). Two-thirds of pts needed dose
reduction during post-remission cycles. Seven (14%) pts [t(8;21)� 5, Inv
16�2] relapsed and with a median follow-up of 34 months (range, 15-54
months) the relapse-free survival rate is 83%. Conclusions: FLAG-GO is a
highly effective regimen and has resulted in high rate of relapse-free
survival in pts with newly diagnosed CBF AML.
6530 Poster Discussion Session (Board #22), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Clinical trial and compassionate use experience with glucarpidase for
methotrexate toxicity. Presenting Author: Brigitte C. Widemann, Pediatric
Oncology Branch, National Cancer Institute, National Institutes of Health,
Bethesda, MD
Background: High dose methotrexate (MTX) is used to treat acute lymphoblastic
leukemia (ALL), osteogenic sarcoma, non-Hodgkin lymphoma
(NHL), and other cancers. MTX-associated renal impairment with delayed
MTX elimination develops after 2 to 10% of treatment cycles, exposing
patients to elevated MTX concentrations with potential for enhanced MTX
toxicity and prolonged hospitalization. Glucarpidase, a recombinant form of
carboxypeptidase G2, rapidly hydrolyzes MTX into inactive metabolites and
provides an alternate way of clearance in patients with delayed MTX
elimination. Methods: From November 1993 to June 2009, 492 patients
experiencing renal toxicity and delayed elimination of MTX were treated
with glucarpidase (50 U/kg intravenously) in compassionate use trials
conducted in the US and EU. Their outcomes are presented here. Results:
The median age of the 492 patients was 18 yrs (range: 5 wks to 85 yrs).
Sixty-three percent were male. Forty-one percent had NHL, 30% osteogenic
sarcoma, 23% ALL, and 7% other malignancies. The median
pre-glucarpidase MTX concentration was 17 �mol/L. Seventy-six percent of
patients received 1 dose of glucarpidase, 22% received 2 doses, and 2%
received 3 doses. The first dose of glucarpidase was given at a median of 3
days after MTX administration. One-hundred and fifty-six patients had MTX
concentrations determined by HPLC. At the first measurement (median 15
minutes post-glucarpidase) MTX was reduced by a median of 99% relative
to the pre-glucarpidase baseline. At the last measurement (median 40 hrs
post-glucarpidase) median MTX reduction remained at 99% compared with
baseline. In 410 patients with pre-glucarpidase renal impairment measured
as CTCAE Grade 2 or higher, 64% recovered to Grade 0 or 1 after a
median of 12.5 days post-glucarpidase. Glucarpidase was well-tolerated
overall; adverse events included paresthesia (2.0%), flushing (1.8%) and
headache (1.0%). Eight percent of patients died within 30 days of
glucarpidase administration of causes unrelated to glucarpidase, as judged
by the treating physician. Conclusions: Glucarpidase is well-tolerated and
reduces MTX concentrations by 99% within 15 min of administration in
patients with impaired renal clearance of MTX.
Leukemia, Myelodysplasia, and Transplantation
423s
6529 Poster Discussion Session (Board #21), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Allogeneic stem cell transplantation for patients over age 65 with acute
myelogenous leukemia and myelodysplastic syndrome. Presenting Author:
Henry Jacob Conter, University of Texas M. D. Anderson Cancer Center,
Houston, TX
Background: ASCT represents a potentially curative approach for AML and
MDS, diseases that primarily affects patients in 7th and 8th decade of life.
Here, we report outcomes of patients older than 64 treated at the MD
Anderson Cancer Center from 1996 until December 2011. Methods: 182
patients older than 64 received an ASCT for AML (n�143) or MDS (n�39).
Outcomes of interest were transplant-related mortality (TRM), incidence of
acute and chronic graft-versus-host disease (GVHD), incidence of relapse,
and overall survival (OS) - which were estimated from the date of
transplant. Results: The median age of patients was 67 (range 65-79). Most
patients were transplanted with active disease (table). Median follow-up for
alive patients was 12.6 months (n�63; range 0-118). The cumulative
incidence of 100-day, 1 year, and 3 year TRM was 14%, 18%, and 21%,
respectively. 26% of patients developed grade II-IV acute GVHD and 35%
suffered from chronic GVHD. The actuarial incidence of relapse was 46% at
1 year and 53% at 3 and 5 years. Actuarial OS was estimated to be 45% at
1 year, 28% at 3 years, and 21% at 5 years. 3 year OS for patients
transplanted in CR and with active disease was 40% versus 23% (p�0.02).
OS of patients age 65-69 or �69 was 30% vs. 20% (p�0.06) at 3 years for
all patients; compared to 38% versus 27% (p�0.23) for patients in those
age groups transplanted in CR. Conclusions: Although a significant minority
of patients older than 64 years may achieve long-term disease control, new
approaches are needed to reduce TRM and relapse in this cohort of
patients.
Category Parameter Number (%)
Donor type Matched related donor 87 (48)
Matched unrelated donor 73 (40)
Mismatched unrelated donor 17 (9)
Preparative regimens Fludarabine/melphalan 85 (47)
Fludarabine/busulfan 61 (34)
Fludarabine/idarubicin 13 (7)
Immunosuppression Tacrolimus/mini-methotrexate 147 (81)
Tacrolimus/mycophenolate 8 (4)
Post-transplant cyclophosphamide 16 (9)
Disease status at ASCT Primary induction failure 21 (12)
Complete remission 1 38 (21)
Complete remission 2 or 3 15 (8)
Refractory/untreated disease 120 (66)
6531 Poster Discussion Session (Board #23), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
BCR-ABL kinase domain mutations and resistance in Ph� acute lymphoblastic
leukemia from the imatinib to the second-generation TKI era.
Presenting Author: Simona Soverini, Department of Hematology/Oncology
Seràgnoli, Bologna, Italy
Background: Advent of 2nd-generation TKIs has brought additional treatment
options for Philadelphia-positive (Ph�) acute lymphoblastic leukemia
(ALL) patients (pts). To analyze the changes they have determined in
mutation frequency and type, we have reviewed the database recording the
results of BCR-ABL mutation analyses done in our laboratory from 2004
through 2011. Methods: 781 tests on 258 pts were performed by direct
sequencing. Results: 143 pts were analyzed because of imatinib resistance;
101 (71%) had one or more mutations (a single mutation in 91 pts; two
mutations in 10 pts). Three mutation types were by far the most frequent:
T315I (38 pts, 37%), E255K (19 pts, 18%) and Y253H (19 pts, 18%). Of
84 pts who had developed resistance to 2nd- or 3rd-line therapy with
dasatinib, nilotinib or bosutinib after imatinib failure, 65 (77%) were
positive for Bcr-Abl mutations; 30 (46%) carried multiple mutations (up to
four) and in 19 of them (63%) this was consequence of multiple lines of
therapy. The most frequent newly acquired mutation in this setting was the
T315I, detected in 35/57 (61%) cases acquiring mutations on dasatinib.
Mutation analysis was also performed in 15 resistant pts enrolled in a study
of dasatinib as 1st-line treatment of Ph� ALL; 12 pts were positive, 11 of
them had a T315I. Taking advantage of a next-generation sequencer
(Roche 454), allowing a high sensitive and quantitative mutation scanning
of Bcr-Abl, serially collected samples from 24 selected cases who developed
mutations and resistance to one or more TKIs were retrospectively
analyzed to study the kinetics of expansion of mutant clones. Results will
be presented. Conclusions: Although 2nd generation TKIs are more potent
and have much fewer insensitive mutations, long-term disease control
remains a problem and the T315I becomes an even tougher enemy. The
high genetic instability fosters mutational events anytime during TKI
treatment and some mutation types (T315I, Y253H) have been observed to
emerge and take over very quickly (from �0.01% to 90% in one-two
months). Supported by PRIN, AIL, AIRC, Fondazione CARISBO.
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