The efficacy of high-dose chemotherapy followed by autologous hematopoietic SCT for relapsed diffuse large B-cell lymphoma (DLBCL) has been reported, but an optimal conditioning regimen has not been determined. This study was conducted to evaluate the safety and efficacy of the MCVAC regimen (consisting of ranimustine (MCNU), cytarabine, etoposide and CY) followed by autologous peripheral blood stem cell transplantation (PBSCT) for patients with high-risk or relapsed DLBCL. A total of 40 patients with DLBCL who received the MCVAC regimen followed by autologous PBSCT were retrospectively evaluated. Median follow-up duration of the surviving patients was 51.2 months (range, 5.4–151.2 months). At 5-year OS and PFS were 73.7% (95% confidence interval (CI), 58.6–88.8) and 62.5% (95% CI, 46.8–78.2), respectively. Although relapse remained the most frequent cause of treatment failure, late-onset adverse events were observed, including two cases of severe pulmonary impairment, and two cases of therapy-related myelodysplastic syndromes (MDS)/AML. In conclusion, the MCVAC regimen would be an effective and tolerable conditioning regimen without TBI for autologous PBSCT for high-risk or relapsed DLBCL. However, late-onset pulmonary toxicity and MDS/AML should be monitored.
First-line treatment of diffuse large B-cell lymphoma (DLBCL) with CHOP or CHOP-like regimens can cure ∼40–50% of patients with aggressive non-Hodgkin's lymphoma. The addition of rituximab significantly improved the remission rate and resulted in an improvement in PFS and OS by 15–20% over CHOP chemotherapy alone.1, 2, 3 However, 20–60% of patients are refractory to initial therapy or relapse after achieving a CR.4 Salvage chemotherapy was effective in 60–70% of patients with refractory or relapsed DLBCL, but could cure no >10% of such patients.5, 6, 7, 8, 9 High-dose chemotherapy followed by autologous hematopoietic SCT has been shown to be superior to salvage chemotherapy alone for patients with chemosensitive relapsed or refractory aggressive non-Hodgkin's lymphoma.10, 11, 12, 13, 14
BEAM, CY plus TBI (CY/TBI) and some other regimens have frequently been used as conditioning regimens for autologous hematopoietic SCT. However, an optimal conditioning regimen which produces the least toxicity and greatest therapeutic efficacy has not been determined.15, 16 High-dose methyl 6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-α-D-glucopyranoside (MCNU; ranimustine), cytarabine, etoposide and CY (MCVAC) chemotherapy was first reported as a conditioning regimen in children, as it possessed a high antitumor activity with acceptable toxicity for lymphoid malignancies.17 We herein reviewed a single institute experience in order to evaluate the safety and efficacy of the MCVAC regimen with autologous peripheral blood stem transplantation (PBSCT) in adult patients with relapsed or high-risk DLBCL.
Patients and methods
Patients who underwent autologous PBSCT following the MCVAC regimen between August 1994 and April 2005 at Keio University Hospital for the treatment of relapsed or high-risk DLBCL were identified from our transplant database, and their demographic as well as transplant data records were collected by chart review. Patients with disease transformation from low-grade B-cell lymphomas were excluded. High-risk DLBCL was defined as partial or no response to initial treatment or high-intermediate/high risk disease according to age-adjusted international prognostic index at initial diagnosis.18 Clinical staging was performed by computed tomography scanning of the neck, thorax, abdomen and pelvis, BM biopsy, cerebrospinal fluid examination and other tools such as magnetic resonance imaging if indicated.
MCVAC regimen, PBSCT and its toxicities
The MCVAC regimen consisted of ranimustine (250 mg/m2 on day −9 and 200 mg/m2 on day −4), cytarabine (2.0 g/m2 twice daily on days −8 to −5), etoposide (200 mg/m2 twice daily on days −8 to −5) and CY (50 mg/kg on days −3 and −2) followed by unpurged PBSCT. On day 0, cryopreserved PBSCs were rapidly thawed at 37 °C and promptly infused into the patient through a central venous catheter. Neutrophil recovery was defined as the first day of three consecutive days with an ANC >0.5 × 109/L. Platelet recovery was defined as the first of three consecutive days with an unsupported platelet count >20 × 109/L.
Non-hematological toxicities without nausea and hair loss were graded according to the Common Terminology Criteria for Adverse Events v3.0.
All patients were managed in high-efficiency particulate air filtered-rooms. Bacterial, fungal, HSV and pneumocystis pneumonitis prophylaxes were given to all patients according to our institutional protocol. Granulocyte colony-stimulating factor was given intravenously from day +1 until neutrophil recovery. The patients were transfused with irradiated blood products to keep the hemoglobin level above 8.0 g/100mL and the platelet count above 20 × 109/L.
CR was defined as the disappearance of any clinically detectable signs of tumor by clinical and laboratory assessment. PR was defined as >50% reduction of detectable tumor. No response was defined as <50% reduction of detectable tumor. Progressive disease was defined as an increase in detectable tumor or the appearance of any new lesion.
OS was defined as the time from transplant until death because of any causes or the last follow-up. PFS was defined as the time from transplant until relapse or progression of lymphoma, or death from any causes, or the last follow-up if none of these events had occurred. TRM was defined as death from any causes other than lymphoma. Survival rates were estimated using the Kaplan–Meier method. Survival curves were compared applying the log-rank test. A P-value of <0.05 was considered statistically significant. Factors that were potentially predictive of OS (P<0.05) and PFS (P<0.05) were entered into a multivariate analysis using the Cox proportion hazards model.
The characteristics of 40 patients at diagnosis and transplant are shown in Tables 1 and 2, respectively. The diagnosis included two patients with mediastinal DLBCL. The nine patients in the first CR at transplant were at high or high-intermediate risk according to age-adjusted 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 transplant was 13.9 months (range, 4.2–198.4). Of the 20 patients who had received radiation therapy before transplant, 7 patients received involved field radiation therapy after chemotherapy for an early-stage disease, 11 patients received radiation therapy for bulky or residual disease after chemotherapy and 2 patients with mediastinal DLBCL received whole-lung radiation therapy. Eight of the patients had received rituximab before transplant.
MCVAC regimen and transplant procedures
In all, 39 patients received the MCVAC regimen as scheduled. One patient did not receive the second dose of CY on day −2 because of progressive impaired performance status due to severe ataxia caused by cytarabine. The median number of infused CD34-positive cells was 4.16 × 106/kg (range, 1.76–39.0 × 106/kg). The median post transplant days of neutrophil recovery and platelet were 9 days (range, 8–19) and 11 days (range, 7–19), respectively.
Toxicities and TRM
Non-hematological treatment-related toxicities within the first 100 days after transplant are shown in Table 3. Prominent toxicities were stomatitis, diarrhea, liver toxicity and infection. Infections included febrile neutropenia (N=30), sepsis (N=4), catheter-related bacteremia (N=3), pneumonia (N=1), cellulitis (N=1) and CMV diseases (N=2). Other less common severe toxicities (grades 3–5) were subdural hematoma (N=1), renal impairment (N=1), myocardial toxicity (N=1), ataxia (N=1) and skin damage (N=2). Veno-occlusive disease of the liver was not observed in any of the patients. Late-onset adverse events included two cases of serious restrictive pulmonary impairment due to pulmonary fibrosis diagnosed at 61.4 and 69.2 months after transplant. One case received radiation therapy to the whole lungs before transplant. Two other patients developed therapy-related myelodysplastic syndrome/AML (MDS/AML), which was diagnosed at 20.3 and 94.7 months after transplant.
Early (within 100 days post transplant) and 4-year overall TRM was 5.0% (95% confidence interval (CI), 0–11.7%) and 9.0% (95% CI, 0–19.0%), respectively.
The causes of TRM included myocardial toxicity in one patient (day +14), CMV pneumonitis in one patient (day +65) and therapy-related MDS/AML in two patients (day +3119 and +830).
Median follow-up duration of 29 patients surviving at the time of the analysis was 51.2 months (range, 5.4–151.2 months). Four patients died of the treatment-related complications described above, and six patients died of disease progression. At 4-years, OS and PFS were 75.0% (95% CI, 55.8–94.2) and 60.1% (95% CI, 38.3–81.9) in patients in CR (N= 22), and 72.5% (95% CI, 49.2–95.8) and 61.1% (95% CI, 38.6–83.6) in patients in non-CR (N=18), respectively. The differences were NS (Figure 1).
In a univariate analysis for factors affecting OS and PFS, only radiation therapy before transplant was significantly associated with unfavorable OS (Table 4). It was also significant with a relative risk of 5.46 (95% CI, 1.2–25.5; P<0.05) by a multivariate analysis. No other factors, including clinical stage, international prognostic index and lactate dehydrogenase values at diagnosis and relapse, number of previous chemotherapy regimens and previous rituximab therapy, had a significant influence on OS and PFS.
The findings of this retrospective study showed that the MCVAC regimen followed by autologous PBSCT in patients with relapsed or high-risk DLBCL was generally well tolerated and yielded about a 60% or higher cure rate of the disease with a low TRM rate (9%). Disease status at transplant has been reported to be the most important prognostic factor influencing outcome in aggressive non-Hodgkin's lymphoma.16, 19 However, disease status at transplant did not have a significant influence on survival in the present study. Although there were a small number of patients and they were evaluated in a retrospective manner, the outcomes suggest that the MCVAC regimen had potential highly curative anti-lymphoma activity for not only high-risk, but also relapsed DLBCL. Furthermore, disease was chemosensitive in 17 of 18 patients not in CR at transplant, which could also contribute to a high survival rate particularly in patients not in CR.
Early toxicities were generally tolerable, and the incidence of TRM within 100 days was limited to 5%, which was identical to those reported in other regimens (3.0–14.8%).16, 19, 20, 21 Late-onset adverse events, however, included therapy-related MDS/AML and severe pulmonary toxicity. Therapy-related MDS/AML has been a well-recognized complication after high-dose chemotherapy, mainly in the setting of autologous hematopoietic SCT for non-Hodgkin's lymphoma. Conditioning regimens, particularly those containing TBI, were initially thought to be responsible for the development of this complication. The agents and intensity of pretransplant chemotherapy have also been reported to be major contributing factors as well as the type of conditioning regimen used for transplant. In a multicenter case–control study, a higher relative risk for developing therapy-related MDS/AML was observed in proportion to the total dosage and duration of pretransplant therapy with alkylating agents.22 In our study, the two patients who developed therapy-related MDS/AML had both received two or three lines of salvage chemotherapy and also radiation therapy before the transplant. The incidence of therapy-related MDS/AML (cumulative incidence of 3.3%) seemed identical to those of other studies.20, 23
In two patients, severe pulmonary impairment developed 61.4 and 69.2 months after transplant. Pulmonary toxicity has been well recognized as a complication related to the use of BCNU-containing regimens. The incidence of non-infectious pulmonary complications associated with BCNU-containing conditioning regimens for autologous hematopoietic SCT such as interstitial pneumonitis has been reported to be 11–26% (Patti et al.,24 Mills et al.,25 Stiff et al.,26 Alessandrino et al.27). BCNU has been implicated as one of the main causes of pulmonary toxicity, particularly in association with previous radiation therapy. In the present study, MCNU, which also has a potent pulmonary toxicity,17 was used instead of BCNU. In contrast, the pulmonary toxicity of MCNU-containing conditioning regimens for autologous hematopoietic SCT has not been evaluated so far. In the present study, one patient received radiation therapy to the whole lungs as a previous therapy, whereas the other patient did not. Therefore, MCVAC without the effect of radiation therapy also has the potential to cause pulmonary toxicity. An accumulation of such cases is needed to elucidate the risk factors for the development of pulmonary toxicity after the MCVAC regimen.
MCVAC regimen was associated with early and late adverse events, which were almost identical to those reported in other regimens, such as BCNU-containing regimens, and considered to provide a high-survival rate in high-risk or relapsed DLBCL patients even in patients not in CR at transplant. Furthermore, as BCNU has been in short supply, MCVAC regimen using MCNU instead of BCNU could be a promising high-dose regimen for high-risk or relapsed DLBCL. We conclude that the MCVAC regimen would be a tolerable, effective and curative conditioning regimen of autologous PBSCT for high-risk or relapsed DLBCL. However, late-onset MDS/AML and adverse effects on the lungs in long-term survivors can occur, and should be carefully monitored.