Outcome with Hyper-CVAD/MTX-Ara-C, a Dose-Intensive Regimen, in Acute Lymphocytic Leukemia and Highly Aggressive Lymphoma in China.

Purpose: The objective of this study was to evaluate the efficacy and potential toxicity of the Hyper-CVAD/MTX-Ara-C regimen,a dose-intensive regimen, in the patients with acute lymphocytic leukemia (ALL) and highly aggressive non-Hodgkin lymphoma (NHL) in China.

PATIENTS AND METHODS: Between June 2004 and June 2007, fifty-six patients with ALL or highly aggressive lymphoma were treated with the Hyper-CVAD/MTX-Ara-C regimen at our institution. Median age was 26 years (range 13 to 60 years), and 35 patients (62.50%) were male. All patients were comprised of 32 previously untreated cases and 24 refractory/relapsed ones. Among the 41 patients with ALL, B-cell disease was present in 82.93%, T-cell disease in 17.07%, and Ph-positive ALL was present in 14.63%, refractory/relapsed disease in 43.90%. Among the 15 patients with highly aggressive NHL, lymphoblastic lymphoma was present in 46.67%, Burkitt’s lymphoma was in 53.33% and refractory/relapsed disease in 40.00%. CNS involvement was present in 8% at diagnosis. Treatment consisted of four cycles of Hyper-CVAD alternating with four cycles of high-dose methotrexate (MTX) and cytarabine therapy, together with intrathecal CNS prophylaxis and aggressive supportive care with granulocyte colony-stimulating factor (G-CSF), transfusion and antibiotic prophylaxis therapy. Maintenance therapy based on cytogenetics and immunophenotypes in most of patients contained 2-year treatment with mercaptopurine, MTX, vincristine, and prednisone (POMP).

RESULTS: The median follow-up time was 7 months (range 1+ to 37+ months). Of the previously untreated 31 patients, twenty-nine patients (93.55%) achieved complete remission (CR) and no patients died during induction therapy. Of the refractory /relapsed 24 patients, fourteen cases (58.33%) achieved CR. Remarkably, the CR rate of the patients with Burkitt’s lymphoma was 75.00% (6/8). The median courses finished during the dose-intensive phase were 4 (range 1 to 8), and the median time to delivery of all eight courses was 10 months. The estimated 3-year overall survival (OS) for the untreated and refractory/relapsed patients with ALL was 46.80% and 28.60%, respectively. Meanwhile, the estimated 2-year OS for the aggressive NHL patients was 84.00%. Compared with the patients with ALL who did not receive CR and get less than four courses of this regimen, the patients who did receive CR and get more than four courses of this dose-intensive regimen showed much better OS (p<0.05). The incidence of CNS relapse was low (5%). Myelosuppression-associated complications including documented infections, fever of unknown origin, hemorrhage were the more frequent side effects. Other significant side effects included neurotoxicity, renal and hepatic toxicities, fatigue, mucositis, nausea, vomiting, diarrhea, skin rashes, and G-CSF therapy-associated bone aches.

CONCLUSION: The present outcome from our single center in China demonstrated that Hyper-CVAD/MTX-Ara-C, a dose-intensive regimen with much higher CR was superior to our previous regimens, even in patients with highly aggressive lymphoma such as lymphoblastic and Burkitt’s lymphoma, and in refractory/relapsed ALL/lymphoma ones. Our study also showed that this regimen was less toxic and well tolerated in most of treated patients in China. Long-term treatment benefits and severe side effects needed further investigation in a well-designed, multiple-center study in China with more eligible patients entering onto the study.