Phase II Study of Nelarabine with Hyper-CVAD in Patients with Previously Untreated T Cell Acute Lymphoblastic Leukemia (T-ALL) and Lymphoblastic Lymphoma (LL)

Hyper-CVAD achieves high rates of complete remission (CR) and improves clinical outcomes in patients (pts) with T-ALL/LL. However, about 50% of pts will relapse. Nelarabine is a novel agent active in relapsed/refractory T lymphoid malignancies, but its activity in frontline therapy of T-ALL/LL remains unclear. We therefore studied the efficacy and safety of nelarabine in combination with hyper-CVAD in frontline therapy for pts with T-ALL/LL.

In this phase II trial we enrolled 36 pts with T-ALL/LL who were treated at our institution from August 2007 to April 2012. Pts received two cycles of nelarabine either during or shortly after the intensified consolidation; two more cycles were given during the maintenance phase. Nelarabine was administered at a dose of 650mg/m²IV daily for 5 days. Pts with bulky mediastinal disease could receive radiation therapy followed by 24 cycles of vincristine, prednisone, mercaptopurine, methotrexate (POMP maintenance). Maintenance cycles 18 and 19 consisted of methotrexate/asparaginase and hyper-CVAD, respectively. CNS prophylaxis included 8 intrathecal treatments of methotrexate alternating with ara-C.

36 pts with T-ALL/LL were enrolled with a median age of 38 years (19–78). Male to female ratio was 26 to 10. Twenty-one pts (58.3 %) had T-ALL, 15 (41.3 %) had LL. Eighteen pts had diploid karyotype; 14 pts had bulky mediastinal disease, and 4 had CNS involvement. Thirty-three (91.6 %) pts achieved CR and 2 (5%) PR. Flow cytometry based MRD negative CR was seen in 8/15 (53%) pts with T-ALL who achieved a CR and had MRD status assessed at the time of CR. With a median follow up duration of 19 months (2–57+), 21 pts (58.3%) are still in remission and alive, 10 (27%) had a relapse (two alive and 8 died) and one pt was lost to follow up, 3 pts did not respond and one died during CR. Probability of CR duration at 3 years was 66%. Three-year probabilities for overall survival (OS) and disease free survival (DFS) were 62% and 61%, respectively. Median OS and DFS have not yet been reached. Thirty (83%) pts had at least one infection grade ≥3. Thrombotic episodes occurred in 6 pts (17%) (4 PE, 2 DVT). Sixteen (44%) pts had G1–2 peripheral neuropathy. Because of neuropathy, the nelarabine dose had to be reduced to 650 mg/m²on alternating days (D1, 3, 5) in two patients and was withheld in another.

Nelarabine can be safely combined with Hyper-CVAD in pts with newly diagnosed pts with T-ALL/LL. The combination of nelarabine with hyper-CVAD is active and can achieve MRD negative CR in T-ALL/LL.

Kantarjian:Genzyme: Research Funding. Thomas:Pfizer: Consultancy, Honoraria; Talon Therapeutics: Honoraria. Ravandi:Genzyme: Research Funding. Burger:Pharmacyclics: Consultancy, Research Funding. Faderl:Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding.