Final report of phase II study of sorafenib, cytarabine and idarubicin for initial therapy in younger patients with acute myeloid leukemia

Sorafenib is a multikinase inhibitor and a potent FLT3 inhibitor that inhibits tumor growth and angiogenesis by inhibiting intracellular Raf kinases and cell surface kinase receptors such as VEGFR, PDGFR-beta, cKIT, and FLT-3.1 It has been approved by the U.S. Food and Drug Administration for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma at a standard dose of 400 mg twice daily. The antileukemic activity of sorafenib has been evaluated in preclinical models and a number of recently reported clinical trials.2 In a phase I/II study, combination therapy with sorafenib, cytarabine, and idarubicin in younger patients with AML was able to induce a high complete response (CR) rate in those with FLT3 mutations and a 1-year probability of survival of 74%.3 We here report long-term outcome for adults with newly diagnosed AML who were treated with a combination of sorafenib, cytarabine, and idarubicin. Details of the patient population and the treatment regimen have been previously published.3 Survival curves were plotted by the Kaplan-Meier method and compared using the log-rank test. Differences in subgroups by different covariates were evaluated using the x2 test for nominal values and Fisher's exact test for continuous variables. Between February 1, 2008, and March 31, 2010, 62 patients with previously untreated AML were enrolled in this study. Patient characteristics are summarized in Table 1a. The median age of the patients was 53 years (range, 18 to 66 years); 12 were older than or equal to 60 years. Twenty-three had FLT3 mutations, including 17 with FLT3-ITD (10 with low mutation burden), 4 with D835 mutation, and 2 with both mutations; 11 patients had antecedent hematologic disorder and 10 had unfavorable cytogenetics. Herein, we will refer to the patients as FLT3-ITD-positive or negative including the 4 patients with sole D835 mutation in the latter group and the 2 with both mutations in the former group. Table 1a Patient characteristics The median white blood cell count (WBC) at presentation was 7.25 × 109/L (range, 0.6 to 228.5 × 109/L). Eight patients were FLT3-ITD–positive/nucleophosmin-1 (NPM1)–negative. The median age of patients with FLT3-ITD mutation was 52 years (range, 20 to 66 years); one had adverse and 18 had intermediate cytogenetics (17 with normal karyotype) based on MRC criteria. Sixty-one patients had response assessment; one patient died before response assessment could be performed. Among these, 49 (79%) achieved CR, and 5 (8%) CRp. Seven (11%) patients were non-responders. Among the 54 responders, 51 patients received consolidation and maintenance courses; 3 proceeded to allogeneic stem cell transplant straight after induction. Patients with FLT3-ITD were more likely to achieve a CR/CRp than were patients without FLT3-ITD [18 of 19 patients (95%) vs. 36 of 43 (84%), respectively (P = 0.23)] (Table 1b). Seventeen FLT3-ITD patients achieved CR and one had CRp, three FLT3-D835 patients achieved a CR and one had CRp, and 32 of 43 patients without FLT3-ITD achieved a CR and four had CRp; one died at induction, and six were resistant to therapy. CR was achieved after one induction cycle in 44 patients and after two induction cycles in five patients. Sixteen patients with the FLT3-ITD mutation achieved CR/CRp after one induction cycle, and two achieved it after two cycles. Altogether, sixteen patients proceeded to allogeneic stem-cell transplantation in first CR/CRp, including nine with a FLT3 mutation (six with FLT3-ITD, three with FLT3-D835). To date, 35 (65%) of the responders have experienced relapse including 11 of 18 patients (61%) with FLT3-ITD and 24 of 36 (67%) without FLT3-ITD (P = 0.69); 33 patients received salvage therapy: 2 died while receiving first salvage therapy, 11 achieved a second CR, 2 CRp, 1 PR and 17 had refractory disease. Ultimately 22 of these 33 patients died after their first or subsequent salvage therapies. Table 1b Response to induction according to FLT3 status With a median follow-up of 52 months (range, 2.3-62.9 months) for all patients, the median OS and DFS were 29 and 13.8 months, respectively (Figure 1a and ​and1b).1b). Figure 1c and ​and1d1d demonstrates the OS and DFS for all patients and for patients with FLT3-ITD. Among patients with FLT3-ITD who achieved CR/CRp, 11 have relapsed and 5 remain in CR; 2 patients died in CR. The median OS and DFS among the 19 patients with FLT3-ITD was 15.5 and 9.9 months, respectively (Figure 1c and ​and1d1d). Figure 1 (a) OS for all patients; (b) DFS for all patients; (c) OS according to FLT3-ITD status; (d) DFS according to FLT3-ITD status. Hematopoietic stem cell transplantation was performed in first CR in 16 of 54 patients who achieved a CR/CRp (30%); six of the 16 relapsed and 7 died following the SCT. The 3-year disease-free survival (DFS) rate (in 54 patients achieving CR/CRp) was 34%; the 3-year OS rate for all patients was 48% (Figure 1a and ​and1b1b). The regimen was generally well tolerated, the adverse events being those expected in patients receiving induction chemotherapy with the combination of cytarabine and idarubicin. The most common grade 3 and 4 adverse events possibly associated with the addition of sorafenib to the induction regimen occurred in 15 patients and included nausea and vomiting (7), cardiac/hypertension (6), diarrhea (5), infections (5), hand and foot syndrome (4), liver toxicity (5), and pancreatitis (2). One patient died of massive myocardial infarction during induction; this was not considered to be related to sorafenib (Table 1c). Table 1c Toxicity Mutations in FLT3 are well-established indicators of poor prognosis in AML 4,5 and occur in approximately 20% to 30% of patients. Small-molecule FLT3 kinase inhibitors have been developed with different efficacies against FLT3-mutant cell lines. They also have been evaluated in FLT3-ITD+ primary leukemia cells, alone or in combination with cytarabine and anthracyclines such as idarubicin. 6,7,8,9 This study reports on the long-term follow-up of patients with newly diagnosed AML who received upfront treatment consisting of sorafenib combined with cytarabine and idarubicin. Nineteen patients had the FLT3-ITD mutation. The response rates (CR and CRp) for patients with FLT3-ITD were higher than that for patients without FLT3-ITD including those with FLT3-D835 mutants and those with wild-type FLT3 (18/19 patients [95%] vs. 36/43 [83%], respectively) although this was not statistically significant (P = 0.23). Similarly, there was no significant difference in OS or DFS when comparing patients with and without FLT3-ITD (Figure 1c and ​and1d).1d). This is in contrast to previous studies reporting significantly shorter DFS and OS for patients with FLT3-ITD and can potentially be attributable to the addition of sorafenib to the regimen. This may be due to the possible increased likelihood of the patients to be able to undergo an allogeneic stem cell transplant as a result of the addition of sorafenib. We also analyzed the outcomes censoring patients at the time of allogeneic stem cell transplant (n=16) and found no significant difference between the groups' outcomes (data not shown). In this study, the sorafenib containing induction regimen produced a high response rate but was associated with relapse in the majority of the patients. Man et al. 10 reported activation of alternative survival pathways in sorafenib-resistant leukemic clones. In their study, 12 of 13 patients with AML and FLT3-ITD responded to treatment with sorafenib monotherapy but nine lost their response at a median of 72 days. We had a similar high response rate in this study but the median DFS was significantly longer at 9.9 months suggesting a potential benefit for combining sorafenib with chemotherapy, especially that overall, the treatment was well tolerated with limited grade 3 and 4 toxicity. A recent report, however, suggested that the addition of sorafenib to standard cytarabine and daunorubicin induction regimen did not improve EFS or OS and was associated with increased toxicity during induction.11 However, the patients treated in that study were older than 60 which may account for the higher incidence of toxicity. Our study is limited due to the inability to discern the impact of other interventions such as allogeneic stem cell transplant, related to its non-randomized design and limited patient numbers. Rollig and colleagues have reported preliminary results of SORAML trial in which patients received cytarabine 100 mg/m2 for 7 days plus daunorubicin 60 mg/m2 for 3 days followed by high dose cytarabine consolidation.12 Patients were randomized to receive Sorafenib at a dose of 800 mg/day or placebo during induction and consolidation and for a 12 months maintenance period after the end of consolidation. Among the 276 patients randomized, 264 were evaluable for event-free survival (EFS), 132 in each arm.12 Patient and disease characteristics were similar between the two arms, with the FLT3-ITD incidence of 16%. The CR rates were 56% and 60% in the placebo and sorafenib arms, respectively (p=0.62). With a median follow-up of 18 months, the median EFS was 12.2 months in the placebo arm and was not reached in the sorafenib arm; the 2-year OS was 66% versus 72% in placebo and sorafenib arms, respectively (p=0.37). Although there was an increased risk of hepatotoxicity and bleeding events in the sorafenib arm, the authors concluded that the addition of sorafenib was associated with a prolongation of EFS which was most marked in the patients with FLT3-ITD.12 The eventual result of this study will better clarify the potential role of sorafenib in the treatment of patients with AML and FLT3-ITD.