6637 Background: Sphingosomal vincristine (SV), a novel formulation of vincristine encapsulated in sphingomyelin/cholesterol liposomes or ‘sphingosomes’ was evaluated for the treatment of multiply relapsed aggressive NHL patients in two studies. While combination chemotherapy is the standard front-line treatment, there remains a substantial need for new effective treatments for multiply relapsed patients. Methods: The Phase IIa and IIb trials were single-arm, open-label studies that evaluated the efficacy and safety of single-agent SV administered at 2.0 mg/m2 every 2 weeks. Primary efficacy endpoint in both studies was the ORR, with time-to-event variables evaluated as secondary endpoints. The Phase IIb study was a multicenter international trial while the Phase IIa was a single-center study. Results: In total 211 patients with aggressive NHL were treated in the Phase IIa (92 pts) and Phase IIb (119 pts) studies. Demographic and baseline characteristics were comparable providing evidence in support of efficacy data pooling. Median age was 62 years and median prior treatments was 3. Two-thirds of patients had disease resistant to their last therapy. The ORR was 28% (7% CR/CRu, 21% PR) with a 95% CI of [22%, 35%]. Estimated median TTP was approximately 4 months and overall median survival was estimated at ∼8.5 months. ORR of 48% and estimated median survival of 27 months was reported in patients with sensitive disease compared to 18% and 6 months for patients with resistant disease. Conclusions: New therapies are needed for patients with multiply relapsed aggressive NHL. Single-agent therapy with SV resulted in clinically meaningful rate of response in this heavily pre-treated population. Patients with sensitive disease had a higher response rate and longer estimated median survival than patients with resistant disease. No significant financial relationships to disclose.

Treatment for patients with stage IV indolent lymphoma ranges from watchful waiting to intensive chemotherapy and stem cell transplantation. In this trial we compared 2 induction regimens followed by 1 year of interferon maintenance therapy. Fludarabine, mitoxantrone (Novantrone), and dexamethasone (FND) were compared with an alternating triple therapy (ATT) regimen (CHOD-Bleo, ESHAP, and NOPP). Maintenance interferon/dexamethasone was given for 1 year in both treatment arms. Endpoints were comparisons of remission rates, survival, failure-free survival (FFS), molecular response rates, and toxicities. One hundred forty-two patients with previously untreated stage IV indolent lymphoma were evaluable (73 on FND; 69 on ATT). The overall response rates were 97% for FND and 97% for ATT (P =.9). The median follow-up is 5.9 years. The 5-year survival rates were 84% with FND and 82% with ATT (P =.9); the 5-year FFS rates were 41% with FND and 50% with ATT (P =.02). In a multivariate analysis, factors predicting for longer FFS were beta(2)-microglobulin less than 3 mg/L (P =.01) and ATT treatment (P =.03). ATT was associated with a substantially higher rate of grade 3-4 toxicities than FND. In conclusion, both regimens were associated with high rates of response and survival. ATT was associated with substantially longer FFS, but it was more toxic than FND.

Peripheral T-cell lymphomas (PTCLs) are an uncommon and heterogeneous group of well-differentiated, post-thymic T-cell malignancies that can present in the skin as cutaneous T-cell lymphomas. In general, their prognosis is poor, and specific therapy is not well defined. We report the successful treatment of a patient with relapsed, refractory PTCL who after failing 13 standard single and multiple chemotherapy regimens and experimental agents had a dramatic prolonged response to diftitoxin denileukin (ONTAK ® ). This fusion protein, composed of diphtheria toxin coupled to interleukin-2, is approved for cutaneous T-cell lymphomas, including mycosis fungoides, and should be considered for treatment of the rare subset of peripheral T-cell lymphomas.

The purpose of the study was to evaluate in patients with recurrent intermediate-grade NHL, the tolerance to and efficacy of an intensive salvage regimen consisting of high doses of ifosfamide, etoposide and mitoxantrone with G-CSF support, followed by autologous stem cell transplantation and to identify prognostic factors for survival in patients with recurrent aggressive lymphoma. Patients with recurrent intermediate-grade NHL under the age of 60 years were eligible. Induction consisted of ifosfamide 10 g/m 2 and etoposide 900 mg/m 2 with G-CSF 5 μg/kg twice a day. Upon recovery, patients underwent stem cell apheresis. Patients achieving complete remission (CR) underwent autologous stem cell transplantation using BEAM conditioning. Those with partial remission (PR) received treatment with ifosfamide 10 g/m 2 , mitoxantrone 20 mg/m 2 and G-CSF 5 μg/kg. Those with CR received BEAM, those with PR received cyclophosphamide 4.5 g/m 2 , etoposide 1200 mg/m 2 and cisplatin 135 mg/m 2 with stem cell rescue followed by BEAM. Antibiotic prophylaxis was given with all treatment cycles. The results were compared with those obtained in a prior study that used MINE-ESHAP salvage. Forty-four patients with recurrent intermediate-grade NHL were enrolled between March 1994 and September 1996. Median age was 50 years (24–61). Eleven patients had transformed lymphoma and seven had a T cell phenotype. Response rate to the high-dose ifosfamide regimen was 77% ± 12% after two cycles and the complete response rate was 41% ± 14%. Myelosuppression was profound but short. Median nadir ANC was 0 and the median duration of ANC <0.5 × 10 9 /l was 6 days (range 3–12). No severe infections occurred; 55% of the patients required blood transfusion and 42% required platelet transfusions. Myelosuppression and transfusion requirements were similar after the first and second cycles. Thirty-five of the 44 patients proceeded to autologous stem cell transplantation and one transplant-related death occurred. With a median follow-up of 52 months, progression-free survival at 2 years is 38% ± 14% and survival is 52% ± 15%. Data from these 44 patients were pooled with data on 53 patients who had received salvage treatment with MINE-ESHAP, for a multivariate analysis of prognostic factors. In multivariate analysis, serum LDH was strongly associated with survival. The use of a more intensive salvage regimen, did not result in a significant increase in long-term outcome, despite a high response rate. In conclusion, duration of treatment, response rates, treatment-related mortality and survival compare favorably with previous salvage regimens, but recurrence remains a major problem. Long-term survival in recurrent large cell lymphoma is influenced more by disease characteristics than by the type of salvage regimen used. Bone Marrow Transplantation (2001) 27, 397–404.

Approximately 3 to 5% of patients with chronic lymphocytic leukemia (CLL) develop an aggressive large cell non Hodgkin's lymphoma (NHL) known as Richter's syndrome (RS). RS has a poor prognosis and a response rate of < 10% with fludarabine-based or other cytotoxic combination regimens. The aim of this study was to evaluate the efficacy and toxicity of the hyperCVXD regimen in RS. Twenty-nine patients, median age 61 years (36–75) 23 males, were treated. Prior diagnosis was CLL in 26 patients, NHL in 2, and Prolymphocytic leukemia in 1. Treatment consisted of fractionated Cyclophosphamide, vincristine, daunoXome and dexamethasone. Six patients (20%) died while receiving study therapy, 4 (14%) during the first cycle of whom 2 had started therapy with overt pneumonia. Grade 4 granulocytopenia occurred in all 95 cycles of therapy with a median time to recovery of 14 days. Twenty three (24%) cycles were complicated by fever, and 15 (15%) by pneumonia. Sepsis was documented in 8 (8%) cycles, and neuropathy in 5 (5%) of cycles. Twenty three patients had a platelet count < 100 × 109/1 prior to therapy: a greater than 50% decrease in platelet count over pre-therapy level occurred in 79% of first cycles, overt bleeding occurred in 4 (4%) of all cycles. Eleven of 29 (38%) patients achieved complete remission (CR), 4 of whom have relapsed after 5, 6, 9, and 12 months of remission. Two of 11 CR patients presented with RS without any prior CLL therapy. One patient had a partial remission. Thus the overall response rate was 12/29 (41%). Overall median survival was 10 months, 19 months in patients who achieved CR, 3 months in those who did not (p=0.0008). A landmark analysis performed at 2 months from start of therapy comparing patients alive in CR versus patients alive but not in CR showed a median survival of 19 months versus 6 months, respectively (p0.0017). In conclusion the hyper CVXD regimen has a relatively high response rate, significant toxicity and a moderate impact on survival in RS.

Six patients with advanced Hodgkin's disease in which multiple conventional treatments (median prior chemotherapy regimens: seven), radiation therapy, and a prior autologous stem cell transplantation (SCT) had failed underwent allogeneic SCT following a fludarabine-based conditioning regimen. Median age was 29 years (22–30). Median time to progression after autologous SCT was 6 months (4–21). Disease status at transplant was refractory relapse (n = 3) and sensitive relapse (n = 3). Cell source was filgrastim-mobilized peripheral blood stem cells from an HLA-identical sibling (n = 4) or matched unrelated donor marrow (n = 2). Conditioning regimens were fludarabine–cyclophosphamide–antithymocyte globulin (n = 4), fludarabine–melphalan (n = 1) and fludarabine–cytarabine–idarubicin (n = 1). Myeloid recovery was prompt, with an absolute neutrophil count ⩾500/μl on day 12 (11–15). Median platelet recovery to ⩾20000/μl was on day 9 (0–60). Chimerism studies on day 30 indicated 100% donor-derived hematopoiesis in 4/5 evaluable patients (4/4 non-progressors). All responders (3/3) have ongoing 100% donor-derived chimerism. Acute graft-versus-host disease (GVHD) was diagnosed in 4/6 evaluable patients. Chronic GVHD was present in 2/4 evaluable patients. There were no regimen-related deaths. Overall day 100 transplant-related mortality was 2/6 (33%). Three patients have expired and three are alive and progression-free with a median follow-up of 9 months (6–26) post transplant. We conclude that allogeneic stem cell transplantation with fludarabine-based preparative regimens is feasible in these high-risk, heavily pretreated HD patients. Bone Marrow Transplantation (2000) 26, 615–620.