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

6584 General Poster Session (Board #20C), Mon, 1:15 PM-5:15 PM
Ofatumumab retreatment and maintenance in patients with fludarabinerefractory
CLL. Presenting Author: Anders Österborg, Karolinska University
Hospital, Stolkholm, Sweden
Background: In Study 406, the anti-CD20 monoclonal antibody ofatumumab
(ofa), given as monotherapy over 6 months, showed 47% overall response rate
(ORR) in patients (pts) with chronic lymphocytic leukemia (CLL) refractory to
fludarabine and alemtuzumab (FA-ref), or to fludarabine with bulky (�5cm)
lymphadenopathy (BF-ref). The effects of ofa retreatment (retx) and maintenance
(mt) are unknown. Methods: Pts who responded to ofa and then progressed
or had stable disease (SD) in Study 406, were offered retx in Study 416
(NCT00802737; GSK/Genmab) with ofa 1 x 300 mg � 7 x 2000 mg weekly
followed by mt with ofa 2000 mg monthly for up to 2 years (if SD or better).
Primary endpoint was ORR (1996 NCI-WG). Safety and time to event outcomes
were also assessed. Results: Of 29 pts enrolled, 7 had SD and 22 had partial
response (PR) and progressed in Study 406. Pts were defined per Study 406: 17
FA-ref, 11 BF-ref, 1 “other”. Pretreatment characteristics were similar between
groups. Pts received a median of 12 doses (range 3-32); 86% had 8 doses, 3%
received all 32 doses. 72% of pts had infusion-related adverse events (AEs),
41% at 1st infusion, mostly grade 1-2. The most common grade �3 AE
occurring up to 60 days after last tx was infection (38%); the most common was
pneumonia (17%). 3 pts (10%) had fatal infections, all bronchopneumonia.
Clinical efficacy is shown in Table. Comparative analysis to Study 406 is
ongoing. Conclusions: The response to ofatumumab (ofa) as induction retreatment
and progression-free survival in this limited number of pts was similar to
1st treatment (Study 406). Ofa maintenance had some clinical benefit for pts
with advanced CLL. Ofa was well-tolerated with no unexpected toxicities.
Efficacy of ofa retx.
FA-ref (n�17) BF-ref (n�11) Total (n�29)
Response %
ORR (95% CI )
At 8 wks (end of weekly retx): 59 (33, 82) 18 (2, 52) 45 (26, 64)
CR 6 0 3
Nodular PR 6 0 3
PR 47 18 38
SD 29 55 38
PD 6 0 3
Not evaluable (NE) 6 27 14
Through 24 wks (4 months mt) 24 (7, 50) 18 (2, 52) 21 (8,40)
Through 52 wks (11 months mt) 24 (7, 50) 18 (2, 52) 24 (10,44)
CR 12 0 7
PR 12 18 17
SD 47 64 52
PD 18 10
NE 12 18 14
Time to event outcomes Median (95% CI), months
Duration of response 11 (7, 11) 24 (NA) 24 (7, 24)
PFS 8 (3, 13) 7 (2,12) 8 (5, 12)
Overall survival 20 (11,28) 11 (5,NA) 18 (11, NA)
6586 General Poster Session (Board #20E), Mon, 1:15 PM-5:15 PM
Albumin as a prognostic factor for overall survival in newly diagnosed
patients with acute myeloid leukemia (AML). Presenting Author: Awais M.
Khan, University of Alabama at Birmingham Comprehensive Cancer Center,
Birmingham, AL
Background: Hypoalbuminemia (HA) is an adverse prognostic factor in
multiple neoplastic diseases. Severe hypoalbuminemia (�3.0 g/dl) at day
�90 post allogeneic hematopoietic cell transplant (AHCT) was reported as
an independent predictive variable for non-relapse mortality and overall
survival (Kharfan-Dabaja, et al Biol Blood Marrow Transplant 2009; 15).
We examined the prognostic value of serum albumin level prior to induction
chemotherapy in patients with newly diagnosed AML. Methods: Data were
collected retrospectively in newly diagnosed AML patients receiving induction
chemotherapy (3� 7 regimen). Primary objective was to examine the
relationship between serum albumin at baseline and probability of achieving
complete remission (CR) or incomplete remission (CRi) and overall
survival (OS). The Kaplan–Meier method used to estimate median overall
survival; chi-square test used for comparison of categorical variables and
t-test for continuous variables. Log rank test used to compare Kaplan–
Meier survival estimates between two groups. Results: Between November
2004 to July 2007, 135 patients who received 3�7 induction chemotherapy
were included. Patient baseline characteristics were similar between
patients with serum albumin � 3.5 g/dl (HA) and those with serum
albumin � 3.5 g/dl (no HA) with respect to age, sex, FAB subtype, history of
antecedent MDS, karyotype, and chemotherapy . In patients with HA, mean
age was 60 years compared to 56.5 years in non HA group. The median OS
for patients with HA was 221 days (95%CI 149.5-292.5) compared to 421
days (95%CI 236.7-605) with normal serum albumin (p�0.005). (Figure-1)
The CR/CRi rate was 64%% for HA and 77.6% for those with normal
albumin (p�0.09). In a multivariable Cox regression analysis including age
� 60 years, history of MDS, karyotype, and serum albumin level at
baseline; only age, karyotype and serum albumin were independent
predictors of OS [Hazard ratio 0.47 (95%CI 0.31-0.71) (p�0.005) for
normal serum albumin group]. Conclusions: In newly diagnosed AML, we
demonstrate that hypoalbuminemia � 3.5 g/dl is an independent covariate
for overall survival with conventional chemotherapy management. The
prognostic value of low serum albumin should be validated in a prospective
study.
Leukemia, Myelodysplasia, and Transplantation
437s
6585 General Poster Session (Board #20D), Mon, 1:15 PM-5:15 PM
Phase I study of TH-302, a hypoxia-activated cytotoxic prodrug, in subjects
with advanced leukemias. Presenting Author: Marina Konopleva, University
of Texas M. D. Anderson Cancer Center, Houston, TX
Background: TH-302 is a 2-nitroimidazole prodrug of the DNA alkylator,
bromo-isophosphoramide mustard designed to be selectively activated in
hypoxic conditions. Preclinical data in mice with ALL have demonstrated
marked expansion of hypoxia in areas of marrow leukemia infiltrates (Benito
et al., PlosOne, in press). TH-302 also exhibited specific hypoxiadependent
cytotoxicity when tested against primary ALL and AML samples
in vitro. Based on these findings, a phase 1 study of TH-302 was designed
for advanced leukemias. Methods: Eligibility: ECOG � 3, relapsed/
refractory leukemias for which no standard therapy options were available,
and acceptable hepatorenal function. A standard 3�3 dose escalation
design was used with 40% dose increments. TH-302 was administered IV
over 30-60 minutes daily on Days 1-5 of a 21-day cycle. The objectives
were to determine the MTD and PK profile of TH-302 with this schedule
and to assess preliminary clinical activity of TH-302. Results: 34 subjects
with previously treated AML (n�26), ALL (n�6) or CML in blast phase
(n�1) received TH-302 at doses of 120 (n�4), 170 (n�4), 240 (n�3),
330 (n�3), 460 (n�16) or 550 (n�4) mg/m². No skin or mucosal toxicity
was noted in participants treated with TH-302 doses �240 mg/m2 .At330
mg/m2 , grade 2 dermatological toxicities included skin ulcer (n�1) and
hand/foot syndrome (n�1). Grade 2 mucositis (n�3) and grade 2 skin
toxicity (e.g. skin rash, skin ulcers; n�3) were reported at 460 mg/m2 ; none
were dose-limiting. Two of 3 evaluable subjects treated at the 550 mg/m2 cohort experienced DLTs of grade 3 esophagitis. Eight subjects had stable
disease or better after 1 cycle. One ALL subject (at 120 mg/m2 ) cleared
marrow blasts with persistent neutropenia. One AML subject (at 550
mg/m2 ) achieved CRp after 1 cycle with resolution of leukemia cutis.
Conclusions: TH-302 administered daily for 5 consecutive days every 3
weeks is well-tolerated with increased incidence of skin and mucosal
toxicity at higher dose levels. Clinical activity has been noted with a few
objective responses, but majority of cytoreductions in the AML subset were
transient. Clinical trials combining TH-302 with various chemotherapeutics
with established efficacy in AML and ALL are planned.
6587 General Poster Session (Board #20F), Mon, 1:15 PM-5:15 PM
Clinical impact of dose intensity of initial tyrosine kinase inhibitor (TKI)
therapy in accelerated-phase CML (CML-AP). Presenting Author: Maro
Ohanian, University of Texas M. D. Anderson Cancer Center, Houston, TX
Background: For patients (pts) presenting with CML-AP, TKIs are recommended.
Although generally well tolerated, dose reductions and/or interruptions
are often required. The impact of TKI dose intensity (DI) on CML-AP
outcome has not been described. Aim: To determine impact of TKI dose
interruptions and/or reductions on outcome in de novo CML-AP. Methods:
Overall, 58 CML-AP pts (median age 46 yrs) were treated on consecutive or
parallel clinical trials with TKIs as initial therapy: imatinib (n�36),
dasatinib (n�5), or nilotinib (n�17). CML-AP features included: blasts
�15% (n�8), basophils �20%, (n�22), platelets �100x109 /L (n�3),
cytogenetic clonal evolution (n�22), or �1 feature (n�3). We examined
the impact of dose reductions, treatment interruptions, and DI (ratio of the
dose received vs. the intended dose for the entire treatment duration) on
event-free (EFS), transformation-free (TFS), and overall survival (OS).
Results: Among 58 pts, 37 required treatment interruptions and/or dose
reductions (29 required dose reductions). 12 pts required dose reductions
and/or interruptions due to hematologic toxicity and 23 for nonhematologic
toxicities. Pts were divided into 3 DI tiers: 100% (n� 21),
90-99%, (n�10), and �90% (n�27). Outcomes were analyzed based on
DI tiers and presence or absence of dose reductions as shown in the table.
Pts with dose reductions and/or interruptions for hematologic toxicities vs.
non-hematologic toxicities had a 24-mo EFS rate of 87% vs. 100%
(p�0.05). 24-mo EFS by dose reductions and/or interruptions within 6 mo
or later were 100% and 91%, respectively (p �0.7). Conclusions: DI has no
significant impact on de novo CML-AP outcome. However, dose interruptions
and/or reductions for hematologic toxicities are associated with worse
24-mo EFS, suggesting myelosuppression may in some patients be more a
feature of the disease than toxicity from therapy.
Outcome % Dose reduced Not reduced P value 100% 90-99%