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

418s Leukemia, Myelodysplasia, and Transplantation
6508 Oral Abstract Session, Mon, 8:00 AM-11:00 AM
A phase Ib/II study evaluating activity and tolerability of BTK inhibitor
PCI-32765 and ofatumumab in patients with chronic lymphocytic leukemia/
small lymphocytic lymphoma (CLL/SLL) and related diseases. Presenting
Author: Samantha Mary Jaglowski, The Ohio State University, Columbus,
OH
Background: Bruton’s tyrosine kinase (BTK) is a non-receptor kinase that is
critical for B-cell receptor (BCR) signaling in normal and malignant B
lymphocytes. PCI-32765 (P), an oral, potent and irreversible BTK inhibitor,
antagonizes BCR signaling in CLL cells and abrogates protective
features of the microenvironment. P is highly active as a single agent in
CLL/SLL patients (pts), and this phase Ib/II study builds upon single-agent
experience by combining P with ofatumumab (O), an anti-CD20 monoclonal
antibody. We present initial safety and efficacy data from cohort 1.
Methods: Pts with relapsed/refractory (R/R) CLL/SLL following �2 prior
therapies (Tx), including a purine-nucleoside analog (PA), are treated with
420 mg P daily, in 28-day cycles, until disease progression. O is added at a
dose of 300 mg on day (D) 1 of cycle 2, followed by 2000 mg on D8, 15,
and 22 of cycle 2, D1, 8, 15, and 22 of cycle 3, and on D1 of cycles 5-8.
Results: As of November 2011, 27 patients with either CLL/SLL/PLL
(n�24) or Richter’s transformation (RT, n�3) have been enrolled and have
received at least 6 cycles of treatment. The median age is 66 (range
51-85), 9 were Rai stage III/IV. Median number of prior Tx is 3 (range
2-10), 15 pts had bulky disease (� 5 cm); 11 pts were PA refractory.
Poor-risk molecular features were common (del(17p) 10 pts, del(11q) 9
pts). No grade (G) 3 or 4 infusion reactions, neutropenia, or thrombocytopenia
have been observed. The majority of adverse events (AE) were G1/2.
G3/4 AE included anemia (11%), pneumonia (11%), UTI (7%), hyponatremia
(7%). 24/24 CLL/SLL/PLL pts have achieved PR (100% ORR) within 6
cycles; 2/3 RT pts had PR. With median follow-up of 6.5 mo (range
5.3-10.2 mo), 23 CLL/SLL/PLL pts and 1 RT pt remain on study; 1
CLL/SLL pt went to transplant in PR; 2 RT pts progressed. Conclusions:
PCI-32765 combined with ofatumumab is well tolerated and highly active
(100% ORR) in pts with heavily pre-treated R/R CLL/SLL. Rapid onset of
response, low relapse rate, and favorable safety profile make this combination
worthy of further study. Cohorts evaluating other Tx sequences are
currently underway.
6510 Poster Discussion Session (Board #2), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
The prognostic significance of early molecular and cytogenetic response for
long-term progression-free and overall survival in imatinib-treated chronic
myeloid leukemia (CML). Presenting Author: Rudiger Hehlmann, Medizinische
Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany
Background: In the face of competing first line treatment options for CML
early prediction of prognosis on imatinib is desirable to assure favorable
survival or otherwise consider the use of an alternative therapy. We sought
to evaluate the prognostic impact of early response landmarks. Methods: A
total of 1,303 newly diagnosed imatinib-treated patients (pts) from the
randomized CML Study IV were investigated to correlate molecular and
cytogenetic response at 3 and 6 months with progression-free and overall
survival (PFS, OS). Median follow-up was 4.7 years (range 0-9). The
BCR-ABL expression was determined by quantitative RT-PCR and standardized
according to the international scale (BCR-ABLIS ). The proportion of
Philadelphia-chromosome positive metaphases (Ph�) was determined by
conventional metaphase analysis. To confirm the prognostic significance of
early molecular response, an independent validation sample of 174 pts
treated with imatinib within the IRIS trial was analyzed. Results: The
persistence of �10% BCR-ABLIS at 3 months separated a high-risk group
(28% of pts; 5-year OS: 87%) from a group with 1-10% BCR-ABLIS (41%
of pts; 5-year OS: 94%; p�0.012), and from a group with �1% BCR-ABLIS (31% of pts; 5-year OS: 97%; p�0.004). By cytogenetics high-risk
patients could be identified by the persistence of �35% Ph� (27% of pts;
5-year OS: 87%) as compared to �35% Ph� (73% of pts; 5-year OS: 95%;
p�0.036). At 6 months the �1% BCR-ABLIS group (37% of pts; 5-year
OS: 89%) showed inferior survival compared to �1% (63% of pts; 5-year
OS: 97%; p�0.001); survival of the �0% Ph� group (34% of pts; 5-year
OS: 91%) was inferior to 0% Ph� (66% of pts; 5-year OS: 97%;
p�0.015). Regarding the IRIS pts 3 month BCR-ABLIS �10% (25% of
pts; 8-year OS: 81%) was associated with inferior survival compared to
�10% (75% of pts; 8-year OS: 93%; p�0.011). Conclusions: Failure to
achieve the response landmarks of 10% BCR-ABLIS or 35% Ph� at 3
months of imatinib treatment and 1% BCR-ABLIS or 0% Ph� at 6 months
identifies high-risk patients which might benefit from an early change of
therapy.
6509^ Poster Discussion Session (Board #1), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Nilotinib versus imatinib in patients (pts) with newly diagnosed chronic myeloid
leukemia in chronic phase (CML-CP): ENESTnd 3-year (yr) follow-up (f/u).
Presenting Author: Hagop Kantarjian, University of Texas M. D. Anderson Cancer
Center, Houston, TX
Background: In ENESTnd, nilotinib significantly reduced progression to AP/BC
and demonstrated superior rates of MMR, MR4 , and MR4.5 vs imatinib with f/u of
2 yrs. Methods: 846 pts with Ph� CML-CP were randomized to nilotinib 300 mg
BID (n � 282), nilotinib 400 mg BID (n � 281), or imatinib 400 mg QD (n �
283). Here, we report 3-yr f/u data. Results: Both nilotinib doses continued to
demonstrate significantly higher rates of MMR, MR4 , and MR4.5 vs imatinib. In a
landmark analysis, pts with BCR-ABL transcript levels � 10% at 3 months (mo)
had a higher probability of achieving MMR by 1 and 2 yrs vs pts with transcript
levels � 10%. No new progressions occurred on treatment since the 2-yr
analysis; rates of progression to AP/BC including events on treatment (n � 2, 3,
12) and those occurring both on treatment and after discontinuation (n � 9, 6,
19) were significantly lower for nilotinib 300 mg BID and nilotinib 400 mg BID
vs imatinib, respectively. At 3 yrs, OS considering only CML-related deaths was
significantly higher for nilotinib vs imatinib. The safety profiles of nilotinib and
imatinib were similar to those at 2 yrs. Conclusions: 3-yr f/u confirms the
superiority of nilotinib vs imatinib and an acceptable tolerability profile for the
treatment of pts with newly diagnosed Ph� CML-CP.
Nilotinib
300 mg BID
(n � 282)
Response by 3 yrs, %
MMR 73
P � .0001
MR4 50
P � .0001
MR4.5 32
Nilotinib
400 mg BID
(n � 281)
Imatinib
400 mg QD
(n � 283)
70
53
P � .0001
44
26
P � .0001
28
15
3-mo landmark analysis: BCR-ABL transcript levels*, %
< 1% (n � 120, 123, 41)
> 1to< 10% (n � 89, 95, 133)
> 10% (n � 24, 28, 88)
Freedom from progression to AP/BC, %
Estimated 3-yr rate on core treatment
P � .0001
76/89
40/67
4/29
99.3
P � .0003
MMR by 1 yr/2 yrs, %
72/91
38/54
14/29
98.7
71/78
31/52
2/20
95.2
Including events after discontinuation
P � .0059
96.7
P � .0185
98.1
93.5
OS, %
Estimated 3-yr OS rate
P � .0496
95.1
P � .0076
97.0
94.0
Only CML-related deaths
P � .4413
98.1
P � .0639
98.5
95.2
Patients with BCR-ABL mutation, n
Any mutation
T315I
P � .0356
11
3
P � .0159
11
2
21
3
* Patients with unevaluable/missing PCR assessments at 3 mo, atypical transcripts, or MMR by 3 mo were
excluded.
6511 Poster Discussion Session (Board #3), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Efficacy and safety of bosutinib (BOS) for Philadelphia chromosome–
positive (Ph�) leukemia in older versus younger patients (pts). Presenting
Author: Tim H. Brummendorf, Universitätsklinikum Aachen, Universitätsklinikum
Hamburg-Eppendorf, Aachen and Hamburg, Germany
Background: BOS is an oral dual Src/Abl kinase inhibitor with potent activity
in Ph� leukemia. Methods: Efficacy and safety of BOS 500 mg/d was
evaluated in older (�65 y; n � 119) and younger (�65 y; n � 451) pts in 3
cohorts: chronic phase chronic myeloid leukemia (CP CML) after imatinib
(IM; CP2L cohort; n � 287); CP CML after IM � dasatinib (DAS) and/or
nilotinib (NIL; CP3L cohort; n � 119); and accelerated/blast phase
(AP/BP) CML or acute lymphoblastic leukemia after IM � DAS and/or NIL
(ADV cohort; n � 164). Results: Baseline events (�65yvs�65 y) included
respiratory disorders (35% vs 13%), cardiac disorders (29% vs 9%), and
diabetes (4% vs 4%). Median baseline medications were 3 (�65 y) and 5
(�65 y). Median BOS duration was 11 mo and median follow-up was 31
mo for all pts. 80% of ³65 y and 67% of �65 y pts discontinued BOS,
including 32% and 18% due to an adverse event (AE; most commonly
thrombocytopenia [6% vs 3%]). Rates of response were similar or lower in
older versus younger pts (Table). On-treatment transformation to AP/BP
CML was similar between groups. Incidences of nonhematologic treatmentemergent
AEs were generally similar between older and younger pts,
notably (all grades/grade �3 for �65yvs�65 y): diarrhea (85%/9% vs
81%/8%), infection (56%/15% vs 49%/10%), and edema (8%/0% vs
4%/�1%). Common grade �3 lab abnormalities (�65yvs�65 y) were
thrombocytopenia (35% vs 35%), neutropenia (21% vs 25%), and anemia
(19% vs 19%). Conclusions: BOS demonstrated similar efficacy and
acceptable safety in both older and younger pts across Ph� leukemia
cohorts.
CP2L CP3L ADV
>65 y 65 y 65 y