Initial Results Of a Phase II Trial Of Sorafenib Plus Standard Induction In Older Adults With Mutant FLT3 Acute Myeloid Leukemia (AML) (Alliance trial C11001)

Sorafenib is an oral multikinase inhibitor that blocks the autophosphorylation and activation of a number of tyrosine kinases; it has potent activity against the FLT3 tyrosine kinase with an internal tandem duplication mutation (FLT3-ITD). Sorafenib has activity against AML with FLT3-ITD mutations as a single agent in the setting of post-transplant relapse (Metzelder et al., Blood 2009) and in combination with chemotherapy for newly diagnosed AML (Ravandi et al., JCO 2010). The prevalence of FLT3 mutations among older adults (>60 years) with AML is not yet well defined. Historical CALGB results using standard chemotherapy for older AML patients with FLT3-ITD have shown a complete remission (CR) rate of 67%, median survival of 0.8 yrs, and 1-yr survival of 30% (Whitman et al., Blood 2010). We hypothesized that the addition of sorafenib to induction and post-remission therapy would improve the overall survival of older patients with FLT3-mutated AML.

We conducted a multicenter, single-arm phase 2 study in patients ≥ 60 years old with newly diagnosed AML (including therapy-related AML) and either a FLT3-ITD or a point mutation in the activation loop of the kinase domain (FLT3-TKD). Subjects with PML-RARA or CBF leukemias were excluded. Induction chemotherapy consisted of cytarabine 100 mg/m² CIVI on days 1-7 and daunorubicin 60 mg/m² IV on days 1-3 (7+3) with oral sorafenib 400 mg bid on days 1-7. Those not achieving a hypoplastic bone marrow on day 14 were to receive 5+2 plus sorafenib 400 mg bid on days 1-7. Patients achieving CR were encouraged to undergo allogeneic HSCT if possible. For all others, consolidation consisted of intermediate-dose cytarabine 2 g/m² over 3 hours on days 1-5 with sorafenib 400 mg bid on days 1-28 for 2 cycles. Following consolidation, maintenance sorafenib 400 mg bid was administered daily for 12 28-day cycles. The primary endpoint for this study is the 1-year overall survival of the FLT3-ITD patients.

A total of 459 older adults were screened for FLT3 mutations though a central laboratory. FLT3 mutations were identified in 81 subjects (17.6%). The median turn-around time for FLT3 testing was 46 hours, with 99.1% of cases returned within the cutoff time of 48 hours. Fifty-two patients to date have enrolled on the study, including 37 with FLT3-ITD (71%) and 15 with FLT3-TKD (29%). The median age is 67 years (range, 60-83) and 19 pts were > 70 years (37%). The median follow up is 4.5 months. Of the 52 evaluable patients, 36 have achieved a CR or CRi (69%) of which 4 were CRi (8%). The CR/CRi rate did not differ between subjects with an ITD (26 of 37, 70%) vs a TKD (10 of 15, 67%). The CR/CRi rate was 58% for those >70 years old. Eight pts are known to have received a second induction course. Four of 52 patients (8%) died within 30 days of starting their most recent induction course with no additional deaths occurring within 60 days. Treatment-related toxicities were those typical during AML induction, and no additional or unexpected toxicities were attributed to sorafenib. There were 2 grade 5 nonhematologic adverse events (lung infection; oral mucositis) and 7 grade 4 events among the first 40 evaluable patients, including infection, cardiac, respiratory, metabolic, and kidney injury.

This study represents the first prospective clinical trial for older adults with AML targeting a specific mutational profile within the US cooperative group setting. It demonstrates the feasibility of rapid screening for FLT3 mutations prior to initial remission induction chemotherapy. The addition of sorafenib to chemotherapy for older adults with AML is associated with a high rate of CR, relatively low risk of mortality during induction, and an acceptable toxicity profile.