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

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6632 General Poster Session (Board #28B), Mon, 1:15 PM-5:15 PM<br />

Post hoc analysis <strong>of</strong> relationship between baseline white blood cell count<br />

and renal and hepatic function and response in a randomized phase III trial<br />

<strong>of</strong> decitabine in patients age 65 or older with acute myeloid leukemia.<br />

Presenting Author: Jacques Delaunay, University <strong>of</strong> Nantes, Nantes,<br />

France<br />

Background: A phase III trial (NCT00260832) in patients (N�485) �65y<br />

with newly diagnosed acute myeloid leukemia (AML) was conducted<br />

(Kantarjian, JCO; in press). Every 4 wk, patients received decitabine (DAC)<br />

20 mg/m 2 (1-h intravenous infusion, 5 successive days) or treatment<br />

choice (TC) with either supportive care or cytarabine (20 mg/m2 subcutaneous<br />

injection daily, 10 successive days). This post hoc analysis examined<br />

whether baseline (BL) renal and hepatic function and white blood cell<br />

(WBC) counts were associated with response to DAC or TC. Methods: For<br />

patients with available data, BL WBC count and markers <strong>of</strong> renal function<br />

(blood urea nitrogen [BUN], creatinine) and liver function (ALT, AST,<br />

albumin) were tabulated for patients with/without a response to DAC or TC.<br />

Response was defined as morphologic complete remission (CR), CR with<br />

incomplete blood count recovery (CRi), or partial remission (PR). Results:<br />

Nonresponders had a higher mean BL creatinine vs responders (86.78 vs<br />

80.23 mmol/L, respectively; P�.005); with no differences in BL BUN<br />

levels. There were no other between-group differences. Conclusions: This<br />

analysis suggests that there is no relationship between BL WBC or hepatic<br />

function and response to treatment with DAC or TC. Although there was no<br />

difference in BL BUN, higher mean creatinine levels in nonresponders may<br />

suggest a prognostic relationship but further studies are needed to clarify.<br />

Parameter<br />

Nonresponder<br />

to DAC or TC<br />

Responder to DAC or TC<br />

(CR�CRi�PR) P value<br />

WBC (10 9 /L)<br />

n 372 101<br />

Mean (SD) 9.25 (13.98) 7.02 (12.25) .118<br />

Median (range) 3.72 (0.33-126.60) 2.70 (0.43-95.57)<br />

ALT (U/L)<br />

n 372 100<br />

Mean (SD) 25.32 (35.53) 20.79 (14.53) .054<br />

Median (range) 18 (5-614) 17 (6-103)<br />

AST (U/L)<br />

n 371 101<br />

Mean (SD) 23.82 (15.93) 21.74 (9.84) .106<br />

Median (range) 20 (5-203) 18 (9-65)<br />

Albumin (g/L)<br />

n 377 102<br />

Mean (SD) 34.18 (5.47) 35.07 (5.34) .139<br />

Median (range) 35 (19-48) 36 (16-44)<br />

BUN (mmol/L)<br />

n 377 102<br />

Mean (SD) 6.97 (2.65) 6.48 (2.27) .064<br />

Median (range) 6.40 (1.3-23.7) 6.15 (2.9-19.5)<br />

Creatinine (mmol/L)<br />

n 377 102<br />

Mean (SD) 86.78 (27.08) 80.23 (18.88) .005<br />

Median (range) 81 (38-254) 78 (44-169)<br />

TPS6634 General Poster Session (Board #29A), Mon, 1:15 PM-5:15 PM<br />

Dasatinib plus SMO antagonist versus dasatinib alone for treating patients<br />

(pts) with newly diagnosed Philadelphia chromosome-positive (Ph�) chronic<br />

myeloid leukemia in chronic phase (CML-CP): Design <strong>of</strong> CA180-363, a<br />

phase II, open-label randomized trial. Presenting Author: Geralyn C.<br />

Trudel, Bristol-Myers Squibb, Montreal, QC, Canada<br />

Background: Dasatinib 100 mg once daily (QD) is approved as first-line<br />

therapy for pts with newly diagnosed Ph� CML-CP and those who are<br />

resistant or intolerant to prior therapy, including imatinib, based on<br />

demonstrated efficacy and tolerability. BMS-833923 (SMO antagonist),<br />

selectively blocks hedgehog (Hh) pathway signaling by binding to and<br />

antagonizing Smoothened (SMO), preventing downstream signaling and<br />

activation <strong>of</strong> target genes. In preclinical studies, SMO loss or inhibition<br />

reduces hematopoietic stem cell renewal, induces CML stem cell depletion,<br />

and inhibits imatinib-resistant CML cell growth (Dierks, Cancer Cell<br />

2008; Zhao, Nature 2009). In pts with CML, Hh signaling genes (Sonic<br />

hedgehog, SMO, and Gli1) are significantly upregulated compared with<br />

control pts (Long, J Exp Clin Cancer Res 2011), suggesting that drug<br />

resistance and disease recurrence may be overcome by targeting the Hh<br />

signaling pathway. Methods: CA180-363 is a phase 2 trial to assess<br />

dasatinib activity with or without SMO antagonist in pts with newly<br />

diagnosed Ph� CML-CP. Pts receive dasatinib 100 mg QD for 12 months<br />

and are then randomized 1:1 to continuing dasatinib 100 mg QD with or<br />

without SMO antagonist up to 24 months, followed by dasatinib 100 mg<br />

QD alone until end <strong>of</strong> study (60 months). Randomization is stratified by<br />

Sokal score at diagnosis and major molecular response (MMR) at 12<br />

months (yes/no). Eligible pts are aged �18 years, have an Eastern<br />

Cooperative Group (ECOG) performance status <strong>of</strong> 0-2, and previously<br />

untreated Ph� CML-CP diagnosed within 6 months <strong>of</strong> enrollment. Primary<br />

endpoint (evaluated in pts who do not achieve MMR prior to randomization)<br />

is comparison <strong>of</strong> MMR rates for dasatinib alone vs dasatinib plus SMO<br />

antagonist. Other endpoints (evaluated in all pts) are complete molecular<br />

response, progression-free survival, event-free survival, transformation-free<br />

survival, and safety <strong>of</strong> the combination regimen. Recruitment started in<br />

September 2011 (14 pts enrolled to date); estimated primary completion<br />

date is November 2014. <strong>Clinical</strong>Trials.gov ID: NCT01357655.<br />

Leukemia, Myelodysplasia, and Transplantation<br />

449s<br />

6633 General Poster Session (Board #28C), Mon, 1:15 PM-5:15 PM<br />

Phase II study <strong>of</strong> short CHOP-rituximab combination with early consolidation<br />

with ibritumomab-tiuxetan-Y90 (IT-Y90 ) in non-pretreated patients age<br />

65 to 80 with CD20� diffuse large B-cell lymphoma (DLBCL). Presenting<br />

Author: Frederic Peyrade, Anticancer Center, Centre Antoine-Lacassagne,<br />

Nice, France<br />

Background: IT-Y90was approved in follicular lymphoma, and some data<br />

indicates that it could be used in DLBCL. It has been reported that early<br />

TEP-TDM negativity is associated with a longer survival in DLBCL, which<br />

suggest that these patients could benefit <strong>of</strong> a less intensive protocol.<br />

Methods: We conducted an international, open-label, phase II nonrandomised<br />

study, in patients aged between 65 and 80 with age-adjusted<br />

(aa) IPI score <strong>of</strong> 0 and 1 and CD20� DLBCL. The primary objective was to<br />

evaluate the efficacy <strong>of</strong> 3 cycles <strong>of</strong> RCHOP14 followed by, in case <strong>of</strong><br />

complete response (CR), an injection <strong>of</strong> IT-Y90 . Results: Thirty patients<br />

(M/F� 1) were included. Median age was 72.6 years (range 65 - 80).<br />

Patients had a stage III/IV, elevated LDH and IPI�1 in 38%, 16.6 and<br />

57% respectively. 25 patients received the full treatment. Five obtained an<br />

uncomplete FDG-PET response and were excluded after 2 RCHOP cycles.<br />

23 patients received the full IT-Y90 dosage (0.4mCi/Kg) and two received<br />

the attenuated dosage (0.3mCi/Kg). Mean treatment time was 54 days<br />

(median 52; min 48-max 69). The CR rate after RCHOP treatment was<br />

85% [95% CI: 65-94]. No treatment-related deaths occurred. Grade III-IV<br />

neutropenia and thrombocytopenia was observed in 45% and 4%, respectively.<br />

Five patients experienced at least one febrile neutropenia. After<br />

IT-Y90 , mean duration time for platelets �50G/l was 2.08 weeks (median<br />

2; min 0-max 5). Two patients required platelet transfusion. With a median<br />

follow-up <strong>of</strong> 29.5 months [95% CI: 23-39], the estimated 3-year PFS was<br />

90% [95% CI: 80-100] and the 3-year OS was 100% [95% CI: 100-100].<br />

Among patients treated with 90Y-IT, only 3 relapsed were recorded (at 6, 16<br />

and 24 months). Conclusions: this study suggested the feasibility, and<br />

efficacy <strong>of</strong> a short regimen including one injection <strong>of</strong> IT-Y90for selected<br />

DLBCL in complete response after 3 cycles <strong>of</strong> RCHOP14. This results need<br />

to be confirmed by further studies.<br />

TPS6635 General Poster Session (Board #29B), Mon, 1:15 PM-5:15 PM<br />

Targeting microenvironment-mediated resistance in leukemias: Phase I<br />

trial <strong>of</strong> mobilization and elimination <strong>of</strong> FLT3-ITD� acute myelogenous<br />

leukemia (AML) stem/progenitor cells by plerixafor/g-CSF/sorafenib. Presenting<br />

Author: Michael Andreeff, University <strong>of</strong> Texas M. D. Anderson<br />

Cancer Center, Houston, TX<br />

Background: FLT3-ITD AML are associated with poor prognosis. We<br />

identified Sorafenib (S) as potent inhibitor <strong>of</strong> FLT3-ITD (Zhang W, JNCI,<br />

2008; Borthakur G., Haematologica, 2010). FLT3-ITD is associated with<br />

overexpression <strong>of</strong> chemokine receptor CXCR4 and we found increased in<br />

vivo activity <strong>of</strong> S combined with CXCR4 inhibitor Plerixafor (P) and G-CSF<br />

(G) (Zeng Z et.al. Blood 2009). Here we report first data testing this<br />

concept in patients with R/R FLT3-ITD AML. Methods: G (10 ug/kg) and<br />

P(240 ug/kg) were given s.c. QOD on days 1 – 13, S (400-600mg), S on d 1<br />

- 28(one cycle). G/P was held when blasts � 5x104/ uL. CD34, 38, 123,<br />

CXCR4 (1D9, 12G5), VLA4, CD44 and phospho-proteins were measured by<br />

flow cytometry. Results: 10 patients have been treated so far : 2 achieved<br />

CRp, 4 PR and 4 failed (NR), for an overall response rate <strong>of</strong> 6/10; 3/6<br />

responders and 4/4 NR were previously treated with FLT3 inhibitors. 4/10<br />

pts. developed hyperleukocytosis (and missed 1 to 5 doses <strong>of</strong> G/P), 6 skin<br />

rash and 3 hypertension. Analysis <strong>of</strong> cells mobilized in 22 cycles revealed a<br />

29-fold increase in WBC, 41-fold in absolute blasts, 77-fold in granulocytes.<br />

Increase in circulating stem/progenitor cells was as follows: CD34�:<br />

231-fold, CD34�/38- : 90-, CD34�/38-/123�(LSC) : 148-, CXCR4�:<br />

139-, VLA-4� : 68- and CD44�: 82-fold. Increase in LSC was correlated<br />

with baseline blasts and VLA4, not with CXCR4. FISH confirmed mobilization<br />

<strong>of</strong> leukemic cells. Increased levels <strong>of</strong> pERK and pAKT were observed in<br />

mobilized cells. Conclusion: The combination <strong>of</strong> G-CSF�Plerixafor appears<br />

superior in increasing circulating leukemic blasts and stem/progenitor cells<br />

in FLT3-ITD AML, as compared to Plerixafor alone in R/R AML(blast<br />

increase 2.1-fold; Uy et al. Blood, in press). Treatment resulted in 2/10<br />

CRp and 4/10 PRs. Mobilized stem/progenitor cells displayed increased<br />

MAPK/AKT signaling and increased CXCR4 expression. This is the first<br />

clinical report <strong>of</strong> G-CSF/Plerixafor for the “mobilization” <strong>of</strong> AML cells,<br />

aimed at removing them from their protective bone marrow microenvironment.<br />

The initial results are providing pro<strong>of</strong>-<strong>of</strong>–principle <strong>of</strong> this concept.<br />

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