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

416s Leukemia, Myelodysplasia, and Transplantation
6500^ Oral Abstract Session, Mon, 8:00 AM-11:00 AM
Effect of anti-CD19 BiTE blinatumomab on complete remission rate and
overall survival in adult patients with relapsed/refractory B-precursor ALL.
Presenting Author: Max Topp, Department of Internal Medicine II, Division
of Hematology and Medical Oncology, Wuerzburg, Germany
Background: Blinatumomab is a bispecific T-cell engaging (BiTE) antibody
that directs cytotoxic T-cells to CD19 expressing target cells. Methods: In
adult patients with relapsed/refractory B-precursor ALL, a phase II dose
ranging trial is being conducted to evaluate efficacy and safety of
blinatumomab. The primary endpoint is the rate of hematological complete
remission (CR) or CR with partial hematological recovery (CRh*) within 2
cycles of blinatumomab treatment. Blinatumomab is administered by
continuous intravenous infusion for 28-days followed by a 14-day treatmentfree
interval. Responding patients can receive 3 additional cycles of
treatment or proceed to bone marrow transplantation. Three dose levels
were explored as shown in the table. Results: In total 36 patients have been
enrolled, 25 are currently evaluable. Seventeen out of 25 treated patients
(68%) reached a hematological CR/CRh* and a minimal residual disease
(MRD) response (MRD level �10 -4 ) within the first 2 cycles. Five out of 17
responders (29%) showed a CRh* due to partial recovery of platelets. For
the first 18 patients, response duration is 7.1 months and the median
follow-up time for overall survival (OS) is 9.7 months (median not reached).
Six cases of relapses have been recorded of which 3 were CD19� , and 3
CD19- . As final dose 5 �g/m²/day in week 1 and 15 �g/m²/day for the
remaining treatment (cohort 2a and 3) was selected. In these cohorts
(n�12), the most common treatment emergent adverse events (TEAEs, all
grade 1-2) were pyrexia (67%), headache (33%) and tremor (33%). TEAEs
of grade �3 (7 in 5 patients, no grade 4), irrespective of relationship, were
infections, confusion, epilepsy, hypertension and thrombocytopenia.
Conclusions: The final dose was well-tolerated and produced an exceptionally
high complete remission rate. A global phase 2 study to confirm these
data is underway.
Summary of dose cohorts and outcomes (Oct 2011).
Cohort
Patients
treated
Week 1, cycle 1
(�g/m 2 /day)
Week 2,
cycle 1
(�g/m 2 /day)
Weeks 3-4,
cycle 1 and
subsequent cycles
(�g/m2 /day) CR/CRh*
1 7 15 15 15 5
2a (final dose) 5 5 15 15 4
2b 6 5 15 30 3
3 (final dose) 7 5 15 15 5
Total 25 17
6502 Oral Abstract Session, Mon, 8:00 AM-11:00 AM
A phase II trial of azacitidine (NSC-102816) and gemtuzumab ozogamicin
(NSC-720568) as induction and post-remission therapy in patients of age
60 and older with previously untreated non-M3 acute myeloid leukemia:
SWOG S0703 protocol—Report on the good-risk patients. Presenting
Author: Sucha Nand, Loyola University Medical Center, Maywood, IL
Background: In pts with AML, response rates to standard chemotherapy
decrease and early death rates increase with age. Whereas pts � 56 yrs of
age have a complete remission (CR) rate of 65% and 30 day mortality risk
of �3%, the respective figures are 33% and 31% in pts � 75 yrs. This trial
was designed to improve safety and efficacy by using agents with low
toxicity, different mechanisms of action and possible synergy. The treatment
could be given in the outpatient setting. Methods: Newly diagnosed
pts with non-M3 AML, 60 yrs or older, were treated as follows: Induction:
Hydroxyurea 1500 mg b.i.d till WBC �10,000/mcL, followed by azacitidine
75 mg/m2/day s/cu or iv days 1-7, gemtuzumab ozogamicin (GO)
3mg/m2 on D8. Induction treatment was repeated for residual disease on
D14. Pts achieving CR received a consolidation treatment identical to the
induction treatment. This was followed by 4 cycles of azacitidine 75/m2/
day, D1-7, given q 4 weeks. Subsequent therapy was optional. Promoter
and global methylation studies were performed at defined time points.
Results: Pts were stratified into good risk (age 60-69 or Zubrod 0-1) and
poor risk (age �70 and Zubrod 2 or 3) groups. The results presented here
are from the good risk cohort. Eighty-three pts were entered of whom 79 are
evaluable. Median age was 71 yrs (60-88) and 49 were males. Thirty-five
achieved CR/CRi (44%: 95% CI 33%-56%). Median overall survival was
11 months and median relapse-free survival with patients achieving a
CR/CRi was 8 months. Six patients (8%), 3 with disease progression, died
within 30 days of registration. The main non-hematologic toxicity was
neutropenic fever (Grade 3 or higher), seen in 27 patients. Conclusions: The
combination of hydroxyurea, azacitidine and GO is associated with a low
induction mortality, can be given in the outpatient setting and produces
results which compare favorably with standard chemotherapy regimens in
elderly patients with AML. Our results are sufficiently encouraging to
warrant further studies of this approach. Clinical Trials.govIdentifier:
NCT00658814.
6501 Oral Abstract Session, Mon, 8:00 AM-11:00 AM
Inotuzumab ozogamycin (I0), a CD22 monoclonal antibody conjugated to
calecheamicin, given weekly, for refractory-relapse acute lymphocytic
leukemia (R-R ALL). Presenting Author: Elias Jabbour, University of Texas
M. D. Anderson Cancer Center, Houston, TX
Background: Patients (pts) with R-R ALL have a poor prognosis. CD22 is
highly expressed in ALL. We have previously reported on 49 pts with R-R
ALL treated with IO at the dose of 1.8 mg/m2 every 3-4 weeks; the overall
response rate was 57%. From preclinical studies, lower dose more frequent
exposure schedules to IO may offer better anti-ALL activity. Methods: Pts
with R-R ALL received IO 0.8 mg/m2 on Day 1, 0.5 mg/m2 on Day 8, and
0.5 mg/m2 on Day 15. The total dose per course remained the same 1.8
mg/m2. Courses were given every 3-4 weeks. Early stopping rules were
implemented for an overall response rate � 40%. Results: 20 pts were
treated so far. Median age was 57 yrs (range 22–84). Cytogenetics were:
Ph� in 7 (35%), t(4:11) in 2 (10%) , diploid in 3 (15%), and other in 8
(40%). CD22 was expressed in � 50% blasts in all pts and in � 90% in 14
(70%). Median number of courses so far was 2 (1–4). 9 (45%) pts received
IO as salvage 1 (S1), 5 (25%) as salvage 2 (S2), 6 (30%) as salvage 3 (S3).
one pt had allo SCT before IO. Median follow-up is 22 weeks (range, 7-43).
Overall, 2/20 pts (10%) achieved CR, 6 had CRp (30%), 2 had marrow CR
(10%), 8 were resistant, 2 died within 4 wks. Overall, CR�CRp�mCR (OR)
was 50%: S1 6/9 (67%); S2 2/5 (40%); S3 2/6 (33%). Of the 10
responders, 7 pts (70%) became MRD negative. There were no clear
correlations between OR and pts/ALL characteristics or with CD22 expression
vs. � 90%. In 16 pts with evaluable pharmacokinetics studies, the
median end of the infusion levels of IO were 117 ng/ml and 77 ng/ml in
responders and non-responders, respectively. Median survival was 7�
months. Median OR duration was 5� months. Median survival in 10
responders has not been reached. Liver function abnormalities (LFA) were
noted as IO related in 7 (35%) pts, severe and reversible in 2 (10%). 4 pts
were able to proceed to allo SCT (1 in CR, 3 in CRp) after a median of 4
weeks from the last infusion of IO; No cases of veno-occlusive disease were
observed. Conclusions: IO given weekly is active in R-R ALL with an OR of
50%. LFAs occur and are reversible. This study of IO weekly schedule is
ongoing. IO and chemotherapy combinations are being pursued.
6503 Oral Abstract Session, Mon, 8:00 AM-11:00 AM
PACE: A pivotal phase II trial of ponatinib in patients with CML and
Ph�ALL resistant or intolerant to dasatinib or nilotinib, or with the T315I
mutation. Presenting Author: Jorge E. Cortes, University of Texas M. D.
Anderson Cancer Center, Houston, TX
Background: Ponatinib is a potent, oral, pan-BCR-ABL inhibitor active
against the native enzyme and all tested resistant mutants, including the
uniformly resistant T315I mutation. Methods: The PACE (Ponatinib Ph�ALL
and CML Evaluation) trial started Sept 2010. Pts with refractory CML (CP,
AP or BP) or Ph�ALL resistant or intolerant (R/I) to dasatinib or nilotinib or
with T315I received 45 mg ponatinib once daily. The trial is ongoing;
enrollment completed Sept 2011. Data as of 17 Jan 2012 are reported.
Results: 449 pts were enrolled, 5 of whom were ineligible (post-imatinib,
non-T315I) but treated. Median age was 59 (18-94) yrs; 53% male.
Diagnoses were: 271 CP-CML (R/I�207; T315I�64); 79 AP-CML (R/
I�60; T315I�19); 94 BP/ALL (R/I�48; T315I�46). Median time from
diagnosis to ponatinib was 6 yrs. Prior TKIs included imatinib (96%),
dasatinib (85%), nilotinib (66%), bosutinib (7%); 94% failed �2 prior
TKIs, 59% failed �3 prior TKIs. 83% had a history of resistance to
dasatinib or nilotinib; 12% were purely intolerant. In CP, best response to
most recent dasatinib or nilotinib was MCyR 25%. Frequent mutations
confirmed at entry: 29% T315I, 8% F317L, 4% E255K, 4 % F359V, 3%
G250E. Median follow-up was 6.6 months. Response rates are presented
in the table. Overall, 64% remained on therapy (77% CP). Most frequent
reasons for discontinuation were progression (12%) and AE (10%). Most
common drug-related AEs were thrombocytopenia (33%), rash (33%), dry
skin (26%). Conclusions: Ponatinib has substantial activity in heavily
pretreated pts and those with refractory T315I. Response rates continue to
improve with longer follow-up. Multivariate analyses of predictors of
outcome will be presented.
n Response to ponatinib / N evaluable (%)
Overall R/I T315I
CP-CML
MCyR* 126/258 (49) 88/197 (45) 38/61 (62)
CCyR 105/258 (41) 70/197 (36) 35/61 (57)
MMR 68/265 (26) 40/205 (20) 28/60 (47)
AP-CML
MHR* 38/57 (67) 31/43 (72) 7/14 (50)
MCyR 27/72 (38) 18/55 (33) 9/17 (53)
CCyR 12/72 (17) 8/55 (15) 4/17 (24)
BP-CML/Ph�ALL
MHR* 33/89 (37) 17/46 (37) 16/43 (37)
MCyR 30/82 (37) 14/41 (34) 16/41 (39)
CCyR 23/82 (28) 11/41 (27) 12/41 (29)
*Primary endpoints: MCyR in CP; MHR in AP, BP/Ph�ALL (baseline MHR excluded).
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