24.12.2012 Views

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

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

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

SHOW MORE
SHOW LESS

You also want an ePaper? Increase the reach of your titles

YUMPU automatically turns print PDFs into web optimized ePapers that Google loves.

438s Leukemia, Myelodysplasia, and Transplantation<br />

6588 General Poster Session (Board #20G), Mon, 1:15 PM-5:15 PM<br />

Impact <strong>of</strong> ABL kinase domain mutations on the outcome <strong>of</strong> patients with<br />

chronic myeloid leukemia (CML). Presenting Author: Kendra Lynn Sweet,<br />

H. Lee M<strong>of</strong>fitt Cancer Center & Research Institute, Tampa, FL<br />

Background: Patients with CML who develop resistance to imatinib commonly<br />

have mutations in the BCR-ABL kinase domain (KDM). Studies<br />

looking at outcomes in patients with P-loop versus non-P-loop mutations<br />

within the ABL-Kinase Domain have produced conflicting results. Methods:<br />

The Total Cancer Care (TCC) database was used to identify patients with<br />

CML treated at M<strong>of</strong>fitt Cancer Center (MCC). Descriptive data were<br />

reported, chi square test was used for categorical variables, and Kaplan<br />

Meier curves were used for OS and PFS. Log rank test was used to compare<br />

survival times between groups. Results: Between 1992 and 2011, 540<br />

CML patients were treated at MCC. Of those, 51% were male and 71% were<br />

under the age <strong>of</strong> 60. Sixty percent (n�322) were diagnosed after 2001. Of<br />

the 540 patients, 6.5% (n�35) were found to have mutations <strong>of</strong> which 26<br />

were detected in patients diagnosed after 2001. Of the 35 patients, 74%<br />

(n�26) had single mutations and 26% (n�9) had compound mutations.<br />

P-loop mutations were seen in 17% (n�6) and 43% (n�15) had T315I<br />

mutations. Patients with KDM progressed to accelerated or blast phase in<br />

46% (n�16) <strong>of</strong> cases compared to 27% (n�136) without mutations<br />

(p�0.03). Median OS was 126 months, 109 months, and not reached in<br />

patients with P-loop, T315I, and non-P-loop mutations respectively<br />

(p�0.17). The corresponding median PFS was 85 months, 89 months, and<br />

not reached (p�0.20). In patients with one mutation median OS was not<br />

reached compared to 105 months in patients with compound mutations<br />

(p�0.27). After 2001, patients with KDM had a median PFS <strong>of</strong> 75 months<br />

and OS <strong>of</strong> 126 months while neither was reached in the non-mutation<br />

cohort (p�0.007, p�0.26 respectively). Median PFS in patients with<br />

single mutations was 85 months versus 10 months in those with compound<br />

mutations (p�0.037). Patients with KDM had additional Ph� clones on<br />

cytogenetics in 49% <strong>of</strong> cases compared with 19% <strong>of</strong> cases in the<br />

non-mutation group (P � 0.005). Conclusions: T315I and P-loop KDM<br />

predict PFS and OS in CML patients, and convey a trend for worse<br />

prognosis. The presence <strong>of</strong> additional Ph� clones in patients with<br />

BCR-ABL KDM indicates a higher level <strong>of</strong> genetic instability and clonal<br />

evolution, which may be the contributing factor to poor outcomes.<br />

6590 General Poster Session (Board #21A), Mon, 1:15 PM-5:15 PM<br />

The large granular lymphocytic leukemia registry: A detailed analysis <strong>of</strong> 79<br />

patients with LGL leukemia and rheumatoid arthritis. Presenting Author:<br />

Kirsten Marie Boughan, Drexel University College <strong>of</strong> Medicine, Philadelphia,<br />

PA<br />

Background: The purpose <strong>of</strong> this study is to analyze patients enrolled in the<br />

LGL leukemia registry to distinguish the similarities between LGL leukemia<br />

and rheumatoid arthritis in order to access overlapping immune mechanisms<br />

that may be responsible for neutrophil mediated destruction.<br />

Methods: A retrospective chart review was performed on 79 patients<br />

enrolled in the LGL registry at Penn State Cancer Institute. All patients<br />

enrolled in the study had a diagnosis <strong>of</strong> both rheumatoid arthritis and<br />

potentially LGL leukemia. Data was collected for age, sex, RF factor<br />

positivity, family history, autoimmune disease, T-cell receptor gene rearrangement,<br />

and bone marrow invasion. Results: Of 79 patients the mean<br />

age <strong>of</strong> onset for LGL leukemia was 60 years old with no discrepancy noted<br />

between sexes, 37 M, 42 F. 49 patients were positive for rheumatoid<br />

factor. 27 patients had rheumatoid arthritis in a first degree relative with no<br />

discrimination between maternal or paternal inheritance. 22 patients were<br />

positive for any other autoimmune process. 60 patients were positive for<br />

T-cell receptor gene rearrangement. Of the remaining 19 patients that were<br />

negative for T-cell receptor rearrangement, 12 had evidence <strong>of</strong> bone<br />

marrow invasion (CD3/CD8� infiltrate in �20% bone marrow) and two<br />

showed bone marrow invasion <strong>of</strong> NK cell LGL (CD3/CD8-, CD57�) (Table).<br />

Conclusions: Patients with T cell LGL leukemia and rheumatoid arthritis<br />

appear to be clinically similar with regard to age, duration <strong>of</strong> disease, and<br />

other autoimmune disorders as patients with rheumatoid arthritis alone.<br />

Our patient population showed those with TLGL and RA also tends to have a<br />

positive family history <strong>of</strong> RA in up to 20% as opposed to 5-10% in RA<br />

patients. Given that RA and TLGL have a significantly higher expression <strong>of</strong><br />

the HLA-DR4 haplotype than healthy patients, it is conceivable that with<br />

shared genetic alterations, and gene environment interactions that may<br />

promote posttranslational modification, there may be a loss <strong>of</strong> tolerance<br />

resulting in T cell activation, and eventual transformation into a T cell<br />

clone.<br />

LGL/RA No. (%) Bone marrow invasion No. (%)<br />

N 79 74<br />

TCR � 60 (75%) 72 (97%)<br />

TCR- 19 (24%) 12 (16%)<br />

6589 General Poster Session (Board #20H), Mon, 1:15 PM-5:15 PM<br />

A phase I/II trial <strong>of</strong> combination <strong>of</strong> PKC412 and 5-azacytidine (AZA) for the<br />

treatment <strong>of</strong> patients with refractory or relapsed (R/R) acute myeloid leukemia<br />

(AML) and myelodysplastic syndrome (MDS). Presenting Author: Aziz Nazha,<br />

University <strong>of</strong> Texas M. D. Anderson Cancer Center, Houston, TX<br />

Background: Midostaurin (PKC412) is a FLT3 kinase inhibitor with activity in<br />

acute myeloid leukemia (AML). Hypomethylating agents play an important role<br />

in the treatment <strong>of</strong> AML and MDS. We investigated the safety (phase I) and<br />

clinical activity (phase II) <strong>of</strong> combination <strong>of</strong> 5-azacytidine (AZA) and PKC412 in<br />

pts with R/R AML and MDS. Method: Pts �18 years with MDS, CMML or AML,<br />

who failed prior therapies with performance status �2, adequate liver (bilirubin<br />

� 2x ULN, ALT � 2.5x ULN) and renal (creatinine � 2x ULN) functions were<br />

eligible. Pts received AZA 75 mg/m2 subcutaneously or intravenously for 7 days<br />

<strong>of</strong> each cycle (Days 1-7) and PKC412 at 25 mg (cohort 1) and 50 mg (cohort 2;<br />

target dose) orally twice daily for 14 days (Days 8-21). Pts were to receive up to<br />

12 cycles if benefit from treatment. Supportive care was standard. Results: 14<br />

pts were included in phase I. 1 pt was inevaluable for DLT (withdrawal before<br />

completing cycle#1). 6 pts treated in cohort 1 and 7 in cohort 2. 1 pt in cohort 2<br />

received PKC412 dose as per cohort 1 dose by pt error. Pt characteristics and<br />

responses are summarized in the Table. The overall response rate (ORR) was<br />

3/13(21%) (2 with CRi, 1 pt dropped BM blasts form 27% to 7% after 2 cycles<br />

and went to transplant. 1/4 with FLT3-ITD achieved CRi, 2 <strong>of</strong> the non-responders<br />

received prior FLT3 inhibitors (1 had developed FLT3 D835). All toxicities were<br />

grade 1 (nausea 1 pt, vomiting 1 pt, dry skin 1 pt, and rash 1 pt) with no<br />

difference between the 2 groups. No DLT was identified. Conclusions:<br />

PKC412�AZA is safe and well tolerated at the intended doses with good ORR in<br />

high risk pts with R/R AML. Phase II study is enrolling pts with FLT3-ITD.<br />

Updated result will be presented.<br />

Patients characteristics and responses.<br />

Parameter<br />

Number 14<br />

Age, years (range) 61 (38-86)<br />

Median N <strong>of</strong> prior therapies, N (range) 1 (1-7)<br />

Dose level, N<br />

Cohort 1 6<br />

Cohort 2 7<br />

Inevaluable (cohort 2) 1<br />

Median N <strong>of</strong> cycles (range) 2 (1-5)<br />

AML history, N (%)<br />

de novo 6 (43)<br />

MDS related 7 (50)<br />

Therapy-related AML 1(7)<br />

Cytogenetic risk group, N (%)<br />

Intermediate 5 (31)<br />

Unfavorable 9 (69)<br />

FLT3-ITD status, N (%)<br />

Positive 4 (29)<br />

Negative 9 (64)<br />

ND 1(7)<br />

Response rate, N (%)<br />

CRi 2 (14)<br />

PR 1(7)<br />

SD 3 (21)<br />

6591 General Poster Session (Board #21B), Mon, 1:15 PM-5:15 PM<br />

Pharmacokinetics (PK) and pharmacodynamics (PD) <strong>of</strong> rituximab administered<br />

by faster infusion in patients with previously untreated diffuse large<br />

B-cell (DLBCL) or follicular lymphoma (FL). Presenting Author: Michael<br />

Brewster, Roche Products Limited, Welwyn Garden City, United Kingdom<br />

Background: Faster infusion <strong>of</strong> rituximab (R) can improve patient (pt)<br />

convenience and reduce strain on oncology unit resources. To assess the<br />

safety, PK and PD <strong>of</strong> a 90-min infusion rate for R in NHL pts, a prospective,<br />

open-label, phase III, multicenter, single-arm trial (RATE) was conducted.<br />

Safety results have been previously presented (ASH 2011). Methods: Pts<br />

(�18 yrs old) with untreated DLBCL or FL, without clinically significant<br />

cardiovascular disease, received R-chemotherapy. R (375 mg/m2 ) was<br />

given at the standard infusion rate (4–6 h) in Cycle 1. Pts who did not<br />

experience Grade 3/4 infusion-related reactions (IRRs) and who had<br />

circulating lymphocyte counts � 5000/�l before Cycle 2, received subsequent<br />

R (375 mg/m2 ) infusions at a 90-min rate: 20% over 30 min then<br />

80% over the next 60 min. Pts (n�14) who completed all cycles at the<br />

90-min infusion rate gave further serum samples up to 16 wks after the last<br />

cycle for determination <strong>of</strong> PK parameters, including R terminal half-life<br />

(t½), maximum serum concentration (Cmax), systemic clearance (CL) and<br />

volume <strong>of</strong> distribution (V). Results: For pts (n�365) that received the<br />

90-min infusion rate at Cycle 2, serum R concentrations increased over the<br />

course <strong>of</strong> the study. Estimated median values were: CL, 107 ml/d; V at<br />

steady state, 3830 ml; t½, 24.6 d. At Cycle 2, 50.5% <strong>of</strong> pts had<br />

undetectable CD19� levels; this percentage increased during the study<br />

(68.3% Cycle 6, 87.5% Cycle 8). Conclusions: Peak R levels were higher<br />

than seen in published data <strong>of</strong> q3w R regimens but comparable with levels<br />

seen for q1w R regimens. The estimated median values for CL, V, t½ and B<br />

cell (CD19�) depletion with the 90-min infusion rate were similar to<br />

previously reported estimates for infusions at the standard rate. These<br />

results, in combination with the safety pr<strong>of</strong>ile previously reported, show<br />

that a faster infusion <strong>of</strong> R can be an acceptable option for selected NHL pts<br />

who tolerated the standard infusion rate at Cycle 1 without a severe IRR.<br />

Serum R concentration (�g/ml)<br />

Cycle 2, Day 1 Cycle 6, Day 1 Cycle 8, Day 1<br />

Trough Peak Trough Peak Trough Peak<br />

N 329 335 241 238 34 36<br />

Mean (SD) 30 (26) 228 (64) 80 (35) 275 (72) 92 (51) 299 (91)<br />

Visit abstract.asco.org and search by abstract for the full list <strong>of</strong> abstract authors and their disclosure information.

Hooray! Your file is uploaded and ready to be published.

Saved successfully!

Ooh no, something went wrong!