Cytoreductive Regimen Containing Ranimustine (MCNU),Carboplatin, Etoposide and Cyclophosphamide (MCEC) Before Autologous Peripheral Blood Stem Cell Transplantation for Relapsed or Refractory Lymphoma
Authors: Asakura Yoshitaka , Tanosaki Ryuji , Kim Sung-Won , Azuma Teruhisa , Kurosawa Saiko , Yakushijin Kimikazu , Maruyama Dai , Mori Shin-ichiro , Fukuda Takahiro , Watanabe Takashi , Kobayashi Yukio , Tobinai Kensei , Takaue Yoichi 
Published: April 2020

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 (Takaue Y, et al. Cancer67:1830, 1991). However, its feasibility and efficacy have not been extensively analyzed in adult patients with lymphoma.

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&lt; 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 &gt;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&gt; 500 /μL and platelets&gt; 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&lt;0.001), bulky disease (P&lt;0.001), disease status other than CR/PR at transplant (P&lt;0.001), stage III–IV (P=0.025), IPI (H or H-I, in NHL, P&lt;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&lt;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&lt;0.001), IPI (HR 2.66; 95% CI 1.19–4.14, P&lt;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.