Clofarabine Plus Low-Dose Cytarabine Induction Followed By Clofarabine Plus Low-Dose Cytarabine Alternating With Decitabine Consolidation In Acute Myeloid Leukemia Frontline Therapy For Older Patients

Background The outcome of elderly patients (pts) with acute myeloid leukemia (AML) treated with currently available therapies remains unsatisfactory. Clofarabine has single agent activity in AML. The combination of clofarabine with low-dose cytarabine produced higher response rates with a comparable safety profile compared with single-agent clofarabine. We previously reported a phase II study of clofarabine + low dose cytarabine followed by prolonged consolidation with clorarabine + low dose cytarabine alternating with decitabine in elderly patients with newly diagnosed AML (Faderl, Cancer 2012). The complete remission (CR) rate was 58%. With median follow up of 31.2 months, the median overall survival (OS) was 12.7 months, and the median relapse free survival was 14.1months. The combination was well tolerated with induction mortality of 3% (Early Death <28 Days), 7% at 8-weeks. Here we report the result with a larger patient population and longer follow up. Material and Methods Pts were eligible if they were >/= 60 years of age with newly diagnosed AML (based on World Health Organization [WHO] criteria) or high-risk myelodysplastic syndrome (MDS; >/=10% blasts or >/= intermediate-2 by the International Prognostic Scoring System) with Eastern Cooperative Oncology Group (ECOG) performance status of </= 2 and adequate organ function (serum total bilirubin </=2 mg/dL, alanine aminotransferase or aspartate aminotransferase </= 4 X the upper limit of normal, serum creatinine </= 2 mg/dL, and cardiac ejection fraction >40%). Induction therapy consisted of clofarabine 20 mg/m2 IV daily X 5 days (1-5) plus cytarabine 20 mg subcutaneously (SC) twice daily (BID) X10 days (1-10). All responses were defined as per IWG criteria (2003). Pts who did not achieve a CR could receive 1 re-induction cycle at the same dose after at least 28 days from C #1. Pts could receive up to 17 cycles of consolidation therapy. Consolidation was administered in blocks of 3 cycles where clofarabine 20 mg/m2 IV daily X 3 days (1-3) plus cytarabine 20 mg SC BID X 7 days (1-7) alternated with decitabine 20 mg/m2IV X5 days (1-5). Consolidation cycles were repeated every 4 to 7 weeks depending on hematopoietic recovery. Results Between 10/21/08 and 10/17/2011, a total of 118 patients were enrolled. The clinical characteristics are summarized in Table 1. The overall response rate (ORR) was 68% (71 [60%] CR, 9 [8%] CRp/CRi). Twenty two (19%) pts required re-induction, 16 (73%) achieved a response (12 achieved CR, 2 CRp, and 2 CRi). Median number of cycles received was 3 (range, 1-19). With median follow up of 31.2 months (range, 9.5-53.9), the median OS was 11.1 (range, 0.2-53.9), EFS 7.7 (range, 0.2-49.5), and relapse-free survival (RFS) 15.9 months (range, 0.3-48.3). The median OS among the responders was 21.1 months (range, 1.3-53.9). Four-week mortality was 3% and 8-week mortality 8%. Adverse events were predominantly grade 2 or less and included (>/= 10%): elevated liver enzymes (53%), elevated bilirubin (42%), diarrhea (19%), nausea (81%), rash (54%), hand and foot syndrome (10%), and elevated creatinine (10%). Grade 3 or more toxicities included: elevated creatinine (3%), rash (2%), vomiting (1%), and hand and foot syndrome (1%). No unexpected toxicities were observed. Conclusion Clofarabine plus low-dose cytarabine followed by prolonged consolidation alternating with decitabine is an active regimen with an ORR of 73% in older patients with newly diagnosed AML and high risk MDS. The regimen was well tolerated with low induction mortality. A randomized trail to compare this combination to best available therapy is needed to further asses the role of this combination in the treatment paradigm of elderly patients with AML. Disclosures: Off Label Use: Clofarabine and decitabine use in AML. Faderl:Sanofi-Aventis: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

Frontline Therapy for Older Patients (pts) with Acute Myeloid Leukemia (AML): Clofarabine Plus Low-Dose Cytarabine Induction Followed by Prolonged Consolidation with Clofarabine Plus Low-Dose Cytarabine Alternating with Decitabine

Abstract 336 Standard therapy (e.g. “3+7”) of newly diagnosed older pts (≥ 60 yrs) with AML is characterized by low response rates, short response durations, and substantial toxicities. New approaches are therefore actively explored in clinical trials. Clofarabine is a second generation deoxyadenosine nucleoside analogue with activity in older pts with frontline AML and presence of unfavorable prognostic factors. In our experience, the combination of clofarabine with low-dose cytarabine achieved higher response rates at no increase of toxicity compared with clofarabine alone (Faderl S et al. Blood 2008). Based on the initial experience, we have designed a combination of lower-dose clofarabine plus low-dose cytarabine induction followed by a prolonged consolidation of these drugs alternating with decitabine to improve survival and maintain the high response rates from the earlier study. Pts were eligible if ≥ 60 yrs of age with newly diagnosed AML. Pts were excluded for ECOG PS > 2, creatinine > 1.5 mg/dL, cardiac ejection fraction < 40%, and prior therapy with clofarabine or decitabine. Induction therapy consisted of clofarabine 20mg/m2 i.v daily × 5 days plus cytarabine 20mg s.c. twice daily × 10 days. Responding pts could receive up to 17 courses of consolidation therapy of clofarabine plus cytarabine (over 3 and 7 days, respectively) during courses 1–2, 6–8, 12–14 alternating with decitabine 20mg/m2 i.v. daily for 5 days during courses 3–5, 9–11, and 15–17. All pts received antibiotic prophylaxis with levofloxacin, valacyclovir and itraconazole (or equivalent). Fifty-nine pts have been accrued with a median age of 70 yrs (range 60–81), of whom 17 pts (29%) were ≥ 75 yrs. Eleven pts (19%) had a PS of 2. Seven pts (12%) had a WBC of > 20,000/mcl at diagnosis. Thirty pts (51%) had abnormal cytogenetics. Molecular profile: FLT3/ITD 5 pts (9%), FLT3/D835 2 (4), NPM1 6 (13), Ras 2 (4). Thirteen pts (22%) had prior MDS (4 pts prior azacitidine; 2 pts prior lenalidomide) and 17 pts (29%) had secondary AML (Hx of prior chemo and/or XRT). Of 57 pts evaluable for response, 35 (61%) achieved CR and 4 (7%) CRp for an ORR of 68%. Six pts (11%) required more than one course to response. The ORR for pts with diploid vs abnormal cytogenetics was 79% vs 57%; for pts with prior MDS 46% vs 82% for pts with neither MDS nor secondary AML. All 7 pts with a FLT3 mutation responded. With a median follow up of 11.6 months (1.1-20.2+), 16 pts relapsed. Responses (CR) are ongoing in 19 pts. Median CR duration is 14.1 mos (1.8-16.4). Six pts (10%) died on study. Only one pt suffered an early death ≤ 28 days from induction (C1D26). Deaths were due to myelosuppression-associated infectious complications. Median overall survival for all 59 pts was 18.1 mos (0.8-20.2+). Median overall survival for responding patients has not been reached. The median number of consolidation cycles received by pts in CR/CRp was 4 (0-14). Fifteen of these pts have so far received at least 6 consolidation cycles. Most toxicities were ≤ grade 2 and included rash (64%), nausea (61%), transaminase elevations (58%), bilirubinemia (51%), diarrhea (32%), mucositis, creatinine evelations, and headache (12% each). Among toxicities > grade 2, transaminase elevations (14%) and bilirubinemia (5%) were most frequent. One pt (65 yr old female) experienced renal failure and pulmonary edema shortly following start of the induction. Myelosuppression and neutropenic fever were common, but prolonged myelosuppression in responders was rare. In summary, clofarabine plus low-dose cytarabine achieves high response rates with a manageable toxicity profile and low induction mortality in pts ≥ age 60 with previously untreated AML. Longer follow up and comparisons with conventional therapy will help establish whether or not this combination also has a survival advantage. Disclosures: Faderl: Genzyme: Honoraria, Research Funding; Eisai: Research Funding. Off Label Use: clofarabine and decitabine in AML. Kantarjian:Genzyme: Research Funding; Eisai: Research Funding.