Cytoreductive Regimen Containing Ranimustine (MCNU),Carboplatin, Etoposide and Cyclophosphamide (MCEC) Before Autologous Peripheral Blood Stem Cell Transplantation for Relapsed or Refractory Lymphoma

Background: Ranimustine (MCNU), a derivative of nitrosourea that was developed in Japan, shows good penetration into cerebrospinal fluid and might be expected to decrease CNS relapse of lymphoid malignancies when used before transplantation (

Patients and Methods: We retrospectively evaluated an MCEC regimen which consisted of MCNU (200 mg/m² on days -8 and -3), carboplatin (300 mg/m² on days -7 through -4), etoposide (500 mg/m² on days -6 through -4) and cyclophosphamide (50 mg/kg on days -3 and -2) in 68 patients with lymphoma (median age, 48 yr: range, 20–65 yr) who underwent autologous peripheral blood stem cell transplantation (PBSCT) at our institution between January 1999 and February 2008. The diagnosis included diffuse large B-cell lymphoma (n=32), T-cell lymphoma (12), Hodgkin lymphoma (9), follicular lymphoma (14), including 6 transformants, and intravascular lymphoma (1). The median time from diagnosis to PBSCT was 20 months (4–198 mo), and the median number of prior chemotherapy regimens was 3 (2–7). Sixty-six patients (97%) had ECOG PS< 2, 28 (41%) had prior XRT, 3 (4%) had bulky disease, 42 (62%) had stage III–IV disease, 19 (28%) had IPI at relapse of high (H) or high-intermediate (H-I), and one had IPS >4. The disease status at transplantation was 1st CR/PR in 10 (15%), ≥2nd CR/PR in 49 (72%), and NC/PD in 9 (13%).

Results: The median number of days to neutrophils> 500 /μL and platelets> 20,000 /μL was 10 (8–19) and 10 (4–30), respectively. The platelet count did not decrease below 20,000 /μL in 9 patients. Grade (G) 4 non-hematological toxicities (CTCAE ver. 3.0) included elevated transaminase (1), hyponatremia of 116 mEq/L (1) and hypokalemia of 2.3 mEq/L (1). GI and CNS toxicities consisted of mucositis (G3, n=10), diarrhea (G3, n=27) and seizure (G2, n=1). G1 interstitial pneumonitis was observed in 5 patients. There were no grade 4 cardiac, pulmonary or renal toxicities except for one patient who died of treatment-related multi-organ failure. The cumulative incidence of relapse at 2 yrs was 49 %. Of 33 relapses, 2 occurred newly in the CNS without any previous history. With a median follow-up of 24 months (3–80) after transplantation for surviving patients, the 2-year overall survival (OS) and progression-free survival (PFS) were 68% (95% CI 55–81%) and 50% (95% CI 38–63%), respectively. In univariate analyses, T-cell phenotype (P<0.001), bulky disease (P<0.001), disease status other than CR/PR at transplant (P<0.001), stage III–IV (P=0.025), IPI (H or H-I, in NHL, P<0.001) and treatment without rituximab (in B-NHL, P=0.004) were unfavorably associated with OS. Multivariate analysis confirmed that T-cell phenotype (HR 1.85; 95% CI 0.85–2.86, P<0.001), bulky disease (HR 3.02; 95% CI 1.26–4.79, P=0.001), disease status at transplant (HR 1.95; 95% CI 0.89–3.01, P<0.001), IPI (HR 2.66; 95% CI 1.19–4.14, P<0.001) and treatment without rituximab (HR 4.12; 95% CI 1.14–7.10, P=0.007) were unfavorably associated with OS.

Conclusion: The results suggested that autologous PBSCT with the MCEC regimen is a feasible and effective treatment option for relapsed/refractory lymphoma.