High-Dose Ara-C, Carboplatin, Etoposide, and Steroids (ACES) Is Effective in Relapse and Refractory Non-Hodgkin Lymphoma

Background

A standard chemotherapy regimen for relapse or refractory non-Hodgkin lymphoma (RR-NHL) is unexplained yet.Although platinum-based therapies, such as dexamethasone, high-dose cytarabine, and cisplatin and etoposide, methylprednisolone, high-dose cytarabine, and cisplatin (ESHAP), are the most commonly used second-line therapies for RR-NHL; nephrotoxicity is a potentially anxious side effect of platinum compounds. In addition, these regimens require a large volume of fluid replacement to prevent nephrotoxicity. ACES comprises carboplatin, 100 mg/m² on days 1-4; etoposide, 80 mg/m² on days 1-4; high-dose Ara-C, 2 g/m² on day 5; and methylprednisolone, 500 mg/day for 5 days from the first day (Niitsu et. al. Eur J Haematol. 1996). However, ACES shows less renal toxicity and gastrointestinal symptoms by replacing cisplatin with carboplatin than that shown by ESHAP. The efficacy and safety of ACES are still unclear because clinical study on ACES regimen for lymphoma is limited. Therefore, we retrospectively evaluated the therapeutic effects and adverse events (AE) in RR-NHL patients who were treated with ACES regimens.

Patients and methods

We analyzed 116 refractory [patients who had not achieved complete response (CR) in the last chemotherapy (n = 78)] and relapse (n = 36) NHL patients who were treated with ACES regimen at our hospital from 2006 to 2016. ACES was performed at every 3 weeks. Among B-cell NHLs (n = 87), 80.4% of patients were treated with rituximab plus ACES. Patients 65 years of age or older were given two-thirds of the standard dose. The median age was 72 years (20-92 years) and median follow-up period was 386 days (29-3177 days). Histological analysis revealed diffuse large B-cell lymphoma (DLBCL) (n = 56), follicular lymphoma (FL) (n = 16), peripheral T-cell lymphoma (PTCL) (n = 19), and other NHLs (n = 25). The ACES regimen was administered as the second-line therapy in 71 (62.2%) patients, and more than third-line therapy in 36 (31%) patients. Sixteen patients underwent auto-PBSCT. We further analyzed the relationships between the clinical outcome [overall response rate (ORR), CR, disease-free survival, and overall survival (OS)], clinical data [sex, patient age (>65 years), performance status (>2), clinical stage (CS>III), IPI (>HI), FLIPI (>HI), number of prior therapies (>2), response to last chemotherapy, period from the last chemotherapy (<60 days), auto-PBSCT], and laboratory parameters [white blood cell count (>5000/µl), lymphocyte count (>1000/µl), platelet count (>15000/µl), LDH (elevated or normal), sIL-2R (elevated or normal), and CRP (elevated or normal)] before initiating ACES regimen. AE were graded according to CTCAE version 4.

Results

The median number of cycles of ACES regimen was 2 (range: 1-11). Among all patients, ORR was 50% with CR 22.4%. ORR in DLBCL, FL, and PTCL were 50%, 68.8%, and 42.1%, and CR rates were 21.4%, 37.5%, and 16.6%, respectively.

The overall median survival duration was 12.6 months; 3- and 5-year OS rates were 33.6% and 30.5%, respectively. Either of CS, elevated CRP, LDH, PS>2, number of previous therapies, response to last chemotherapy, sIL-2R, or period from the last chemotherapy was significantly associated with shorter OS (P= 0.026, P < 0.001, P= 0.003, P= 0.002, P= 0.03, P < 0001, P= 0.001, and P < 0.001, respectively). In multivariate analysis, LDH, period from the last treatment, and CRP were significantly associated with a decreased CR rate (P = 0.049, P = 0.034, and P = 0.004, respectively). The 3-year OS rate in DLBCL, FL, and PTCL were 35.2%, 62.1%, and 32%, respectively. OS was significantly longer in FL than in DLBCL and PTCL (P = 0.027).

Hematological AE of grade 3 or higher included neutropenia in 90.5% and thrombocytopenia in 70.6% of patients; sepsis and pneumonia developed in two patients. Increased serum creatinine level of grade 3 or higher was observed only in 8.6% [grade 2 (n = 7), grade 3 (n = 3)].

Conclusion

In this study, we analyzed a relatively large number of patients with NHL who were treated with ACES. Although this study included many patients with unfavorable factors such as older age, more than third-line therapy and refractory treatments before ACES, response rates, and OS were comparable with other salvage regimens including ESHAP. In ACES, carboplatin was administrated without continuous hydration, and renal toxicity was less than that in ESHAP. Therefore, we suggest that ACES is an option for treatment of RR-NHL.