MCVAC) Regimen Followed by Autologous Peripheral Blood Stem Cell Transplantation for High-Risk Diffuse Large B-Cell Lymphoma
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Bone Marrow Transplantation (2011) 46, 923–928 & 2011 Macmillan Publishers Limited All rights reserved 0268-3369/11 www.nature.com/bmt ORIGINAL ARTICLE Safety and efficacy of high-dose ranimustine, cytarabine, etoposide and CY (MCVAC) regimen followed by autologous peripheral blood stem cell transplantation for high-risk diffuse large B-cell lymphoma J Kato1,2, T Mori1, K Yokoyama1, Y Tsukada1, T Ueda1,2, T Shimizu1 and S Okamoto1 1Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan and 2Novartis Pharma Program for Clinical Therapeutics of Hematologic Malignancy, Keio University School of Medicine, Tokyo, Japan The efficacy of high-dose chemotherapy followed by Introduction autologous hematopoietic SCT for relapsed diffuse large B-cell lymphoma (DLBCL) has been reported, but an First-line treatment of diffuse large B-cell lymphoma optimal conditioning regimen has not been determined. (DLBCL) with CHOP or CHOP-like regimens can cure This study was conducted to evaluate the safety and B40–50% of patients with aggressive non-Hodgkin’s efficacy of the MCVAC regimen (consisting of ranimus- lymphoma. The addition of rituximab significantly im- tine (MCNU), cytarabine, etoposide and CY) followed by proved the remission rate and resulted in an improvement autologous peripheral blood stem cell transplantation in PFS and OS by 15–20% over CHOP chemotherapy (PBSCT) for patients with high-risk or relapsed DLBCL. alone.1–3 However, 20–60% of patients are refractory to A total of 40 patients with DLBCL who received the initial therapy or relapse after achieving a CR.4 Salvage MCVAC regimen followed by autologous PBSCT were chemotherapy was effective in 60–70% of patients with retrospectively evaluated. Median follow-up duration of refractory or relapsed DLBCL, but could cure no 410% of the surviving patients was 51.2 months (range, 5.4–151.2 such patients.5–9 High-dose chemotherapy followed by months). At 5-year OS and PFS were 73.7% (95% autologous hematopoietic SCT has been shown to be confidence interval (CI), 58.6–88.8) and 62.5% (95% CI, superior to salvage chemotherapy alone for patients with 46.8–78.2), respectively. Although relapse remained the chemosensitive relapsed or refractory aggressive non- most frequent cause of treatment failure, late-onset Hodgkin’s lymphoma.10–14 adverse events were observed, including two cases of BEAM, CY plus TBI (CY/TBI) and some other regimens severe pulmonary impairment, and two cases of therapy- have frequently been used as conditioning regimens related myelodysplastic syndromes (MDS)/AML. In for autologous hematopoietic SCT. However, an optimal conclusion, the MCVAC regimen would be an effective conditioning regimen which produces the least toxicity and and tolerable conditioning regimen without TBI for greatest therapeutic efficacy has not been determined.15,16 autologous PBSCT for high-risk or relapsed DLBCL. High-dose methyl 6-[3-(2-chloroethyl)-3-nitrosoureido]-6- However, late-onset pulmonary toxicity and MDS/AML deoxy-a-D-glucopyranoside (MCNU; ranimustine), cytar- should be monitored. abine, etoposide and CY (MCVAC) chemotherapy was Bone Marrow Transplantation (2011) 46, 923–928; first reported as a conditioning regimen in children, as it doi:10.1038/bmt.2010.243; published online 25 October 2010 possessed a high antitumor activity with acceptable toxicity Keywords: diffuse large B-cell lymphoma; autologous for lymphoid malignancies.17 We herein reviewed a single peripheral blood stem cell transplantation; high-dose institute experience in order to evaluate the safety and chemotherapy; MCVAC regimen; pulmonary toxicity efficacy of the MCVAC regimen with autologous periph- eral blood stem transplantation (PBSCT) in adult patients with relapsed or high-risk DLBCL. Patients and methods Patients Patients who underwent autologous PBSCT following the Correspondence: Dr T Mori, Division of Hematology, Department of MCVAC regimen between August 1994 and April 2005 at Medicine, Keio University School of Medicine, 35 Shinanomachi, Keio University Hospital for the treatment of relapsed or Shinjuku-ku, Tokyo 160-8582, Japan. E-mail: [email protected] high-risk DLBCL were identified from our transplant Received 15 March 2010; revised 14 June 2010; accepted 12 August 2010; database, and their demographic as well as transplant data published online 25 October 2010 records were collected by chart review. Patients with disease MCVAC regimen for DLBCL J Kato et al 924 transformation from low-grade B-cell lymphomas were Results excluded. High-risk DLBCL was defined as partial or no response to initial treatment or high-intermediate/high risk Patient characteristics disease according to age-adjusted international prognostic The characteristics of 40 patients at diagnosis and index at initial diagnosis.18 Clinical staging was performed transplant are shown in Tables 1 and 2, respectively. The by computed tomography scanning of the neck, thorax, diagnosis included two patients with mediastinal DLBCL. abdomen and pelvis, BM biopsy, cerebrospinal fluid The nine patients in the first CR at transplant were at examination and other tools such as magnetic resonance high or high-intermediate risk according to age-adjusted imaging if indicated. international prognostic index at diagnosis.18 Disease was chemosensitive in 18 patients not in CR at transplant, except for 1 patient. Median time from diagnosis to MCVAC regimen, PBSCT and its toxicities transplant was 13.9 months (range, 4.2–198.4). Of the 20 The MCVAC regimen consisted of ranimustine (250 mg/m2 patients who had received radiation therapy before on day À9 and 200 mg/m2 on day À4), cytarabine (2.0 g/m2 transplant, 7 patients received involved field radiation twice daily on days À8toÀ5), etoposide (200 mg/m2 twice therapy after chemotherapy for an early-stage disease, 11 daily on days À8toÀ5) and CY (50 mg/kg on days À3 and patients received radiation therapy for bulky or residual À2) followed by unpurged PBSCT. On day 0, cryopre- disease after chemotherapy and 2 patients with mediastinal served PBSCs were rapidly thawed at 37 1C and promptly infused into the patient through a central venous catheter. Neutrophil recovery was defined as the first day of three Table 1 Patient characteristics at diagnosis (N ¼ 40) 9 consecutive days with an ANC 40.5 Â 10 /L. Platelet Median age, years (range) 49 (22–59) recovery was defined as the first of three consecutive days Sex, no. of male/no. of female 16/24 with an unsupported platelet count 420 Â 109/L. Non-hematological toxicities without nausea and hair Stage I–II 10 loss were graded according to the Common Terminology III–IV 30 Criteria for Adverse Events v3.0. B symptoms A27 Supportive care B13 All patients were managed in high-efficiency particulate air filtered-rooms. Bacterial, fungal, HSV and pneumocystis LDH pneumonitis prophylaxes were given to all patients accord- Normal 12 Elevated 25 ing to our institutional protocol. Granulocyte colony- Unknown 3 stimulating factor was given intravenously from day þ 1 until neutrophil recovery. The patients were transfused with No. of extranodal sites irradiated blood products to keep the hemoglobin level 0–1 10 9 117 above 8.0 g/100mL and the platelet count above 20 Â 10 /L. 2 or upper 13 Performance status Response criteria 0–1 26 CR was defined as the disappearance of any clinically 2–4 13 detectable signs of tumor by clinical and laboratory Unknown 1 assessment. PR was defined as 450% reduction of International prognostic index detectable tumor. No response was defined as o50% Low risk 14 reduction of detectable tumor. Progressive disease was Low-intermediate risk 7 defined as an increase in detectable tumor or the High-intermediate risk 13 appearance of any new lesion. High risk 5 Unknown 1 Statistical analysis Bulky disease OS was defined as the time from transplant until death Yes 8 No 32 because of any causes or the last follow-up. PFS was defined as the time from transplant until relapse or BM involvement progression of lymphoma, or death from any causes, or Yes 30 the last follow-up if none of these events had occurred. No 9 Unknown 1 TRM was defined as death from any causes other than lymphoma. Survival rates were estimated using the CNS involvement Kaplan–Meier method. Survival curves were compared Yes 2 applying the log-rank test. A P-value of o0.05 was No 32 considered statistically significant. Factors that were Unknown 6 potentially predictive of OS (Po0.05) and PFS (Po0.05) were entered into a multivariate analysis using the Cox Abbreviations: CNS ¼ central nervous system; LDH ¼ lactate dehydro- proportion hazards model. genase. Bone Marrow Transplantation MCVAC regimen for DLBCL J Kato et al 925 Table 2 Patient characteristics at transplant (N ¼ 40) Table 3 Toxicities within 100 days after transplantation (N ¼ 40) Median age, years (range) 50.5 (23–61) Gradea Median time from diagnosis to transplant, 13.9 (4.2–198.4) months (range) 012345 Stage Stomatitis 0 1 8 31 0 0 CR 22 Diarrhea 1 2 18 19 0 0 1st CR 9 Liver 1 9 15 14 1 0 2nd CR 13 CNS hemorrhage 39 0 0 1 0 0 Non-CR 18 Ataxia 39 0 0 1 0 0 Cardiac 38 0 0 1 0 1 Performance status Renal 16 20 3 1 0 0 0–1 38 Cystitis 22 16 2 0 0 0 22Skin 38 0 0 2 0 0 Previous radiation therapy Infection Yes 20 Febrile neutropenia — 0 30 0 0 No 20 Sepsis — 0 4 0 0 Catheter-related bacteremia — 0 3 0 0 No. of regimens before transplant Pneumonia — 0 1 0 0 14Cellulitis — 0 1 0 0 228CMV disease — 0 1 0 1b 438 Abbreviation: CNS ¼ central nervous system. Previous rituximab therapy aGrades were determined according to the Common Terminology Criteria Yes 8 for Adverse Events v3.0.