Blood (ASH Annual Meeting Abstracts) 2010 116: Abstract 3286
`© 2010 American Society of Hematology
`Poster Session
`
`Acute Myeloid Leukemia - Therapy, excluding Transplantation: Poster III
`Update of a Phase I/II Trial of 5-Azacytidine Prior to
`Gemtuzumab Ozogamicin (GO) for Patients with Relapsed
`Acute Myeloid Leukemia with Correlative Biomarker
`Studies
`Edward D. Ball, MD1, Bruno C. Medeiros, MD*,2, Larissa Balaian, PhD1, Tracy Roque*,3,
`Sue Corringham*,3, Richa Rajwanshi*,4, Steven Coutre*,4, Jason R Gotlib, MD, MS*,2, Asad
`Bashey, MD, PhD5 and Karen Messer*,3
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`1 Moores UCSD Cancer Center, Univ. of California at San Diego, La Jolla, CA, USA,
`2 Stanford University School of Medicine, Stanford, CA, USA,
`3 Moores UCSD Cancer Center, Univ. of California at San Diego, La Jolla, CA,
`4 Stanford University School of Medicine, Stanford, CA,
`5 BMT Group of Georgia, Atlanta, GA, USA
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`Abstract 3286
`
`Acute myeloid leukemia (AML) cells express the cell surface antigen CD33 that is a down-
`regulator of cell growth when ligated by a monoclonal antibody in a Syk-dependent manner. The
`response of AML cells to gemtuzumab ozogamicin (GO) also depends on Syk and SHP-1
`expression (Leukemia 20:2093, 2006). The hypomethylating agent 5-azacytidine (5-aza) induced
`re-expression of Syk in some cases, therefore increasing the sensitivity of originally Syk-
`negative, non-responsive cells to CD33 ligation to levels of Syk-positive cells. We initiated a
`phase 1/2 clinical trial examining if treatment with 5-aza prior to GO is safe, efficacious, and
`whether in vivo responses to GO correlated with Syk expression and induction by 5-aza. Here we
`update the interim results of this trial (NCI registration number NCT00766116). In Phase I, 14
`patients (9 males, 5 females), age range: 39–82 years [median: 66]) were treated with 75mg/m2
`5-aza daily and GO in a dose-escalation manner, 4 cohorts total. The first cohort (n=3) received
`5-aza for 2 days followed by GO at 3 mg/m2 on days 3 and 17; the second cohort (n=3) received
`5-aza for 2 days followed by GO at 6 mg/m2 on days 3 and 17; the third cohort (n=4) received 5-
`aza for 4 days followed by GO at 6 mg/m2 on days 5 and 19; and the fourth cohort (n=4) at 5-aza
`for 6 days followed by GO at 6 mg/m2 on days 7 and 21. There were no responses in the first 2
`cohorts. One patient in cohort 3 achieved CR, and 2 in cohort 4 achieved CR and CRp. Adverse
`events ( Grade 3) included febrile neutropenia 36%, infection 14%, pancytopenia 7%, dyspnea
`7%, and retinopathy 7%. Average length on study (n=14) was 45 days with a mortality rate of
`14% (unrelated to treatment). No dose-limiting toxicities were encountered in phase I, therefore
`the MTD is the dose in cohort 4. The overall response rate in evaluable patients in phase I (n=11)
`is 27%. Average time to ANC recovery (n=6): 30 days (range 15–42, median 33 days). In Phase
`II, 10 patients (5 males, 5 females), age range: 29–64 years (median 60) were treated at the MTD:
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`5-aza for 6 days and GO at 6 mg/m2 on days 7 and 21. 8 patients were in 1st relapse, 1 in 2nd and
`1 in 3rd. There were 3 responders (2 CR, 1 CRp) in this phase, all in 1st relapse at baseline.
`Adverse events ( Grade 3) include febrile neutropenia 50%, infection 20%, increased LFTs
`10%, thrombocytopenia 10%, dyspnea 10%, wheezing 10%, mucositis 10%, cough 10%, and
`hypoalbuminemia 10%. The average length on study (n=10) was 40 days with a mortality rate of
`10% (not related to study treatment). Average time to ANC recovery in phase II (n=2): 15 days
`(range 12–17, median 15) with an overall response rate in evaluable patients (n=7) of 43%. The
`ORR for phase I/II (n=18) is 33%. 21 of the 24 patient sample pairs have been analyzed for Syk
`and SHP-1 expression (one patient did not have a baseline sample). Prior to therapy, Syk was
`expressed in 16 of 20 cases. After 5-aza treatment, Syk was re-expressed in all 4 negative cases,
`and increased over baseline in one case that was previously Syk +. SHP-1 was positive in 17 of
`the 20 cases and was re-expressed in all 3 negative cases. Leukemia cells from patients who
`achieved CR were Syk+ in 3 of 5 cases (the 6th hasn't been analyzed). Syk was re-expressed in
`the two negative cases after 5-aza. SHP-1 was expressed in 4 of 5 cases at baseline, and re-
`expressed in the one negative case after 5-aza. In vitro we analyzed inhibition of proliferation (for
`patients 1–6) or colony formation (for patients 7–24) induced by 5-aza and GO. 5-aza alone
`allowed 62.3+/–3.5 survival of leukemia cells and GO alone allowed survival of 59.5+/–1.7
`leukemia cells. However, exposure to both agents resulted in a survival rate of 24.8+/–1.6
`(P<0.05, Students t-test). We also compared pre- and post 5-aza samples from the same patients:
`in all cases 5-aza treatment increased the GO-mediated cytotoxicity from 39.4+/–3.1 to 66.8+/–
`2.4 ((P<0.05, Students t-test). These data show that in vivo exposure to 5-aza can induce the
`expression of two biomarkers involved in the response to GO. This ongoing study indicates the
`combination of 5-aza and GO is well-tolerated, that Syk and SHP-1 are modulated by 5-aza in
`vivo, and that complete responses have been noted with this combination.
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`Disclosures: Ball: Celgene: Equity Ownership, Research Funding. Off Label Use: Will discuss
`use of 5-azacytidine (Vidaza) for treatment of relapsed AML in combination with Mylotarg (on
`label, but only as monotherapy). Medeiros: Celgene: Research Funding, Speakers Bureau;
`Novartis: Research Funding, Speakers Bureau; Merck: Research Funding; Genentech: Research
`Funding; Alexion: Speakers Bureau.
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`Footnotes
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`* Asterisk with author names denotes non-ASH members.
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