Intensification of Hyper-CVAD with L-Asparaginase, Vincristine, and Dexamethasone ("Augmented Hyper-CVAD") Has Activity in Adult Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL).

Few treatment options exist for adults patients (pts) with relapsed/refractory ALL and prognosis for these pts remains poor. The hyper-CVAD program (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) has been established as an active induction regimen with a 91% CR rate and 5-yr. survival of 39% (Kantarjian et al. JCO 18:547, 2000). Following this lead, we designed an “augmented” hyper-CVAD (AHCVAD) combination intensifying the doses of vincristine, L-asparaginase, and dexamethasone during induction and consolidation. In this phase II study, pts received up to 8 courses of HCVAD alternating with methotrexate and high-dose cytarabine. With each course, pts received L-asparaginase 20,000 units i.v. and vincristine 2 mg i.v. at days 1, 8, and 15 each, and dexamethasone 80 mg i.v./p.o. on days 1–4 and 15–18. From June 2003 to July 2007, 55 pts with relapsed/refractory ALL have been enrolled. Median age was 34 yrs (range 14–70). Forty-one pts (75%) had pre-B ALL (2 pts with isolated CNS disease and one with an isolated testicular mass), 12 (22%) T cell ALL (2 with isolated extramedullary disease), 1 (2%) pt mature B ALL, and 1 (2%) biphenotypic leukemia. Karyotype was diploid in 25 (45%) pts and abnormal in 27 (49%) pts (1 Ph+ ALL). Median number of prior regimens was 1 (1–6). Median remission duration to the initial induction regimen was 11.5 mos (1–68). Seven (13%) pts were primary refractory. Forty-nine pts are evaluable for response (1 too early, 5 off study for toxicity or pt choice). Twenty-two (45%) pts achieved CR, 3 (6%) PR, and 4 (8%) hematologic improvement (HI). Median remission duration following AHCVAD was 4.75 mos (range, 0.2–45.5+). Twelve (24%, 8 in CR, 1 in PR, 1 with HI) pts proceeded to receive a stem cell transplant. Eight (15%) died while on study from infectious complications. Uncomplicated neutropenic fever was common. Three pts (5%) were intolerant to L-asparaginase and had to be taken off study early. Intensification of hyper-CVAD with asparaginase, vincristine, and dexamethasone is active in ALL salvage producing a CR rate of 45%. Further improvements should include:

1. identification of salvage pts with maximum chance of response;

2. combination with new drugs and attempts to prolong remission duration for these pts.