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

438s Leukemia, Myelodysplasia, and Transplantation
6588 General Poster Session (Board #20G), Mon, 1:15 PM-5:15 PM
Impact of ABL kinase domain mutations on the outcome of patients with
chronic myeloid leukemia (CML). Presenting Author: Kendra Lynn Sweet,
H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
Background: Patients with CML who develop resistance to imatinib commonly
have mutations in the BCR-ABL kinase domain (KDM). Studies
looking at outcomes in patients with P-loop versus non-P-loop mutations
within the ABL-Kinase Domain have produced conflicting results. Methods:
The Total Cancer Care (TCC) database was used to identify patients with
CML treated at Moffitt Cancer Center (MCC). Descriptive data were
reported, chi square test was used for categorical variables, and Kaplan
Meier curves were used for OS and PFS. Log rank test was used to compare
survival times between groups. Results: Between 1992 and 2011, 540
CML patients were treated at MCC. Of those, 51% were male and 71% were
under the age of 60. Sixty percent (n�322) were diagnosed after 2001. Of
the 540 patients, 6.5% (n�35) were found to have mutations of which 26
were detected in patients diagnosed after 2001. Of the 35 patients, 74%
(n�26) had single mutations and 26% (n�9) had compound mutations.
P-loop mutations were seen in 17% (n�6) and 43% (n�15) had T315I
mutations. Patients with KDM progressed to accelerated or blast phase in
46% (n�16) of cases compared to 27% (n�136) without mutations
(p�0.03). Median OS was 126 months, 109 months, and not reached in
patients with P-loop, T315I, and non-P-loop mutations respectively
(p�0.17). The corresponding median PFS was 85 months, 89 months, and
not reached (p�0.20). In patients with one mutation median OS was not
reached compared to 105 months in patients with compound mutations
(p�0.27). After 2001, patients with KDM had a median PFS of 75 months
and OS of 126 months while neither was reached in the non-mutation
cohort (p�0.007, p�0.26 respectively). Median PFS in patients with
single mutations was 85 months versus 10 months in those with compound
mutations (p�0.037). Patients with KDM had additional Ph� clones on
cytogenetics in 49% of cases compared with 19% of cases in the
non-mutation group (P � 0.005). Conclusions: T315I and P-loop KDM
predict PFS and OS in CML patients, and convey a trend for worse
prognosis. The presence of additional Ph� clones in patients with
BCR-ABL KDM indicates a higher level of genetic instability and clonal
evolution, which may be the contributing factor to poor outcomes.
6590 General Poster Session (Board #21A), Mon, 1:15 PM-5:15 PM
The large granular lymphocytic leukemia registry: A detailed analysis of 79
patients with LGL leukemia and rheumatoid arthritis. Presenting Author:
Kirsten Marie Boughan, Drexel University College of Medicine, Philadelphia,
PA
Background: The purpose of this study is to analyze patients enrolled in the
LGL leukemia registry to distinguish the similarities between LGL leukemia
and rheumatoid arthritis in order to access overlapping immune mechanisms
that may be responsible for neutrophil mediated destruction.
Methods: A retrospective chart review was performed on 79 patients
enrolled in the LGL registry at Penn State Cancer Institute. All patients
enrolled in the study had a diagnosis of both rheumatoid arthritis and
potentially LGL leukemia. Data was collected for age, sex, RF factor
positivity, family history, autoimmune disease, T-cell receptor gene rearrangement,
and bone marrow invasion. Results: Of 79 patients the mean
age of onset for LGL leukemia was 60 years old with no discrepancy noted
between sexes, 37 M, 42 F. 49 patients were positive for rheumatoid
factor. 27 patients had rheumatoid arthritis in a first degree relative with no
discrimination between maternal or paternal inheritance. 22 patients were
positive for any other autoimmune process. 60 patients were positive for
T-cell receptor gene rearrangement. Of the remaining 19 patients that were
negative for T-cell receptor rearrangement, 12 had evidence of bone
marrow invasion (CD3/CD8� infiltrate in �20% bone marrow) and two
showed bone marrow invasion of NK cell LGL (CD3/CD8-, CD57�) (Table).
Conclusions: Patients with T cell LGL leukemia and rheumatoid arthritis
appear to be clinically similar with regard to age, duration of disease, and
other autoimmune disorders as patients with rheumatoid arthritis alone.
Our patient population showed those with TLGL and RA also tends to have a
positive family history of RA in up to 20% as opposed to 5-10% in RA
patients. Given that RA and TLGL have a significantly higher expression of
the HLA-DR4 haplotype than healthy patients, it is conceivable that with
shared genetic alterations, and gene environment interactions that may
promote posttranslational modification, there may be a loss of tolerance
resulting in T cell activation, and eventual transformation into a T cell
clone.
LGL/RA No. (%) Bone marrow invasion No. (%)
N 79 74
TCR � 60 (75%) 72 (97%)
TCR- 19 (24%) 12 (16%)
6589 General Poster Session (Board #20H), Mon, 1:15 PM-5:15 PM
A phase I/II trial of combination of PKC412 and 5-azacytidine (AZA) for the
treatment of patients with refractory or relapsed (R/R) acute myeloid leukemia
(AML) and myelodysplastic syndrome (MDS). Presenting Author: Aziz Nazha,
University of Texas M. D. Anderson Cancer Center, Houston, TX
Background: Midostaurin (PKC412) is a FLT3 kinase inhibitor with activity in
acute myeloid leukemia (AML). Hypomethylating agents play an important role
in the treatment of AML and MDS. We investigated the safety (phase I) and
clinical activity (phase II) of combination of 5-azacytidine (AZA) and PKC412 in
pts with R/R AML and MDS. Method: Pts �18 years with MDS, CMML or AML,
who failed prior therapies with performance status �2, adequate liver (bilirubin
� 2x ULN, ALT � 2.5x ULN) and renal (creatinine � 2x ULN) functions were
eligible. Pts received AZA 75 mg/m2 subcutaneously or intravenously for 7 days
of each cycle (Days 1-7) and PKC412 at 25 mg (cohort 1) and 50 mg (cohort 2;
target dose) orally twice daily for 14 days (Days 8-21). Pts were to receive up to
12 cycles if benefit from treatment. Supportive care was standard. Results: 14
pts were included in phase I. 1 pt was inevaluable for DLT (withdrawal before
completing cycle#1). 6 pts treated in cohort 1 and 7 in cohort 2. 1 pt in cohort 2
received PKC412 dose as per cohort 1 dose by pt error. Pt characteristics and
responses are summarized in the Table. The overall response rate (ORR) was
3/13(21%) (2 with CRi, 1 pt dropped BM blasts form 27% to 7% after 2 cycles
and went to transplant. 1/4 with FLT3-ITD achieved CRi, 2 of the non-responders
received prior FLT3 inhibitors (1 had developed FLT3 D835). All toxicities were
grade 1 (nausea 1 pt, vomiting 1 pt, dry skin 1 pt, and rash 1 pt) with no
difference between the 2 groups. No DLT was identified. Conclusions:
PKC412�AZA is safe and well tolerated at the intended doses with good ORR in
high risk pts with R/R AML. Phase II study is enrolling pts with FLT3-ITD.
Updated result will be presented.
Patients characteristics and responses.
Parameter
Number 14
Age, years (range) 61 (38-86)
Median N of prior therapies, N (range) 1 (1-7)
Dose level, N
Cohort 1 6
Cohort 2 7
Inevaluable (cohort 2) 1
Median N of cycles (range) 2 (1-5)
AML history, N (%)
de novo 6 (43)
MDS related 7 (50)
Therapy-related AML 1(7)
Cytogenetic risk group, N (%)
Intermediate 5 (31)
Unfavorable 9 (69)
FLT3-ITD status, N (%)
Positive 4 (29)
Negative 9 (64)
ND 1(7)
Response rate, N (%)
CRi 2 (14)
PR 1(7)
SD 3 (21)
6591 General Poster Session (Board #21B), Mon, 1:15 PM-5:15 PM
Pharmacokinetics (PK) and pharmacodynamics (PD) of rituximab administered
by faster infusion in patients with previously untreated diffuse large
B-cell (DLBCL) or follicular lymphoma (FL). Presenting Author: Michael
Brewster, Roche Products Limited, Welwyn Garden City, United Kingdom
Background: Faster infusion of rituximab (R) can improve patient (pt)
convenience and reduce strain on oncology unit resources. To assess the
safety, PK and PD of a 90-min infusion rate for R in NHL pts, a prospective,
open-label, phase III, multicenter, single-arm trial (RATE) was conducted.
Safety results have been previously presented (ASH 2011). Methods: Pts
(�18 yrs old) with untreated DLBCL or FL, without clinically significant
cardiovascular disease, received R-chemotherapy. R (375 mg/m2 ) was
given at the standard infusion rate (4–6 h) in Cycle 1. Pts who did not
experience Grade 3/4 infusion-related reactions (IRRs) and who had
circulating lymphocyte counts � 5000/�l before Cycle 2, received subsequent
R (375 mg/m2 ) infusions at a 90-min rate: 20% over 30 min then
80% over the next 60 min. Pts (n�14) who completed all cycles at the
90-min infusion rate gave further serum samples up to 16 wks after the last
cycle for determination of PK parameters, including R terminal half-life
(t½), maximum serum concentration (Cmax), systemic clearance (CL) and
volume of distribution (V). Results: For pts (n�365) that received the
90-min infusion rate at Cycle 2, serum R concentrations increased over the
course of the study. Estimated median values were: CL, 107 ml/d; V at
steady state, 3830 ml; t½, 24.6 d. At Cycle 2, 50.5% of pts had
undetectable CD19� levels; this percentage increased during the study
(68.3% Cycle 6, 87.5% Cycle 8). Conclusions: Peak R levels were higher
than seen in published data of q3w R regimens but comparable with levels
seen for q1w R regimens. The estimated median values for CL, V, t½ and B
cell (CD19�) depletion with the 90-min infusion rate were similar to
previously reported estimates for infusions at the standard rate. These
results, in combination with the safety profile previously reported, show
that a faster infusion of R can be an acceptable option for selected NHL pts
who tolerated the standard infusion rate at Cycle 1 without a severe IRR.
Serum R concentration (�g/ml)
Cycle 2, Day 1 Cycle 6, Day 1 Cycle 8, Day 1
Trough Peak Trough Peak Trough Peak
N 329 335 241 238 34 36
Mean (SD) 30 (26) 228 (64) 80 (35) 275 (72) 92 (51) 299 (91)
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