Phase II Study of High Dose Outpatient Cyclophosphamide and Rituximab, without Stem Cell Support, for Low Grade and Mantle Cell Lymphoma.

Background: High dose cyclophosphamide and rituximab may be as or more effective than traditional myeloablative regimens, and less toxic. Prior work at our institution has shown that stem cell support is unnecessary after high-dose cyclophosphamide, in patients treated for aplastic anemia. Although initial response rates to myeloablative chemotherapy and autologous stem cell transplant for low grade lymphomas are high, eventual disease relapse is frequent, and both short and long term toxicities are substantial. One possible reason for the failure of therapy is the re-infusion of tumor cells with the stem cell product. Since high-dose cyclophosphamide will not eradicate stem cells, stem cell support should not be necessary, obviating the risk of reinfusing lymphoma cells. This phase II study was undertaken to determine the safety and efficacy of this approach in low grade and mantle cell lymphoma. Patients and Methods: Eligible lymphomas included chronic lymphocytic leukemia/small lymphocytic lymphoma, marginal zone, follicular grade I or II, and mantle cell lymphoma. Eligibility criteria included age ≥18 years, platelet count ≥75,000/mm3, WBC ≥3,000/mm3, bone marrow involvement ≤10%, and at least a partial response to the most recent prior therapy. Treatment consisted of rituximab 375 mg/m2 on days 1, 4, 8, and 11 followed by cyclophosphamide 50 mg/kg/day IV daily for 4 days, given on days 15–18, pegfilgrastim 6 mg on day 20, and rituximab 375 mg/m2 on days 45 and 52. All treatment was given in an outpatient setting with close monitoring, and without planned hospitalization. Results: As of August 6, 2006, forty-four patients (31M:13F), median age 55 years (range 24–70 ) have been accrued, with the following histologies: CLL/SLL (n=3), follicular lymphoma grade I or II (n=19), marginal zone lymphoma (n=1), and mantle cell lymphoma (n=21). 36 of the 44 patients have completed high dose cyclophosphamide and rituximab. Twenty four patients had received only 1 previous regimen, generally 4–6 cycles of R-CHOP to maximal response immediately prior to study enrollment. On completion of therapy, 26 (72%) patients had CR, and 10 (28%) patients maintained PR. Median follow up from completion of therapy is 12 months (range 2–34 months). Three patients have had disease progression, at a median of 13 months (range, 6–15 months). Of the 17 patients with mantle cell lymphoma, none have had disease progression. All patients recovered counts rapidly: neutrophils > 500/mm3 at a median of 10 days following cyclophosphamide (range 7–17), and platelets > 20,000/mm3 at 9 days (range 0–23). The most common grade 3 or 4 non-hematologic toxicities included pain (21%), nausea and vomiting (6%), infection (6%), abnormal LFT (3%), syncope (3%). Nine patients required a period of hospitalization for management of neutropenic fever, 6 for other problems. There have been no fatal toxicities. Conclusions: High-dose cyclophosphamide and rituximab, without stem cell support, can be given safely to patients with low grade and mantle cell lymphoma who have received prior chemotherapy. Toxicity is significantly lower than traditional myeloablative autologous transplant regimens, the risk of tumor cell reinfusion is avoided, and the option of a later myeloablative allogeneic transplant in the event of relapse is not compromised. This treatment was administered safely in an outpatient setting, and early efficacy results are encouraging.