A multi-institutional phase II trial of a novel inpatient schedule of continuous interleukin-2 with interferon alpha-2b in advanced renal cell carcinoma: major durable responses in a less highly selected patient population.

BACKGROUND: A prospective multi-institutional phase II trial was undertaken to define the activity and toxicity of a unique decrescendo infusion of interleukin-2 (IL-2) in combination with interferon (IFN) in patients with metastatic renal cell carcinoma. The identical regimen has shown promise in advanced melanoma. PATIENTS AND METHODS: Between February 1997 and March 1999, 47 patients with metastatic renal cell carcinoma, from five institutions, were treated with outpatient s.c. IFN (10 mU/m2/day) on days 1-5, followed by inpatient IL-2 via continuous i.v. decrescendo infusion [18 million International Units (MIU) (I mg)/m2/6 h, followed by 18 MIU/m2/12 h, then 18 MIU/m2/24 h and 4.5 MIU/m2/24 h for the following 3 days] on days 8-12, in a hospital ward without intensive care unit (ICU)-type monitoring. Treatment was repeated every 4 weeks. In contrast to high dose IL-2 protocols, patient eligibility did not require pulmonary function tests and allowed serum creatinine up to 2 mg/dl. RESULTS: Among 44 eligible patients, 57% (25) had their primary in place, 57% (25) had bone or visceral involvement, and only 4% (2) had lung as their only site of disease. The overall response rate in 43 response-evaluable patients was 16.3% [95% confidence interval (CI) 5.3 to 27.3], with three complete responses and four partial responses observed. The median survival was 13 months; nine patients remain alive at >23 months. The median duration of response is 36 months (range 11.5 to 48+ months). Toxicity was modest, consisting of typical cytokine-induced systemic symptoms and rare organ dysfunction. Severe grade 4 toxicity occurred in only 13% of the 130 cycles. CONCLUSIONS: This unique, reasonably well tolerated IL-2/IFN combination induced a modest response rate with a number of durable remissions. While the optimal IL-2-based regimen for the treatment of advanced renal cell carcinoma remains elusive, the present regimen should attract considerable interest. This is based on tumor activity very similar to high dose IL-2 in a patient population not as carefully selected for optimal organ function.

Pilot trial of interleukin-2 with granulocyte colony-stimulating factor for the mobilization of progenitor cells in advanced breast cancer patients undergoing high-dose chemotherapy: expansion of immune effectors within the stem-cell graft and post-stem-cell infusion.

PURPOSE: To evaluate whether administration of interleukin-2 (IL-2) with granulocyte colony-stimulating factor (G-CSF) improves mobilization of immune effector cells into the stem-cell graft of patients undergoing high-dose chemotherapy and autografting. PATIENTS AND METHODS: We performed a trial of stem-cell mobilization with IL-2 and G-CSF in advanced breast cancer patients receiving high-dose chemotherapy with cyclophosphamide, thiotepa, and carboplatin and stem cells followed by IL-2. The trial defined immune, hematologic, and clinical effects of IL-2 in this setting. RESULTS: Of 32 patients enrolled, nine received G-CSF alone for mobilization. Twenty-one of 23 patients mobilized with IL-2 plus G-CSF had stem cells collected with more mononuclear cells than those receiving G-CSF (19.3 v 10.4 x 10(8)/kg; P =.006), but fewer CD34(+) progenitor cells (6.9 v 22.0 x 10(6)/kg; P =.049). The IL-2 plus G-CSF-mobilized patients had greater numbers of activated T (CD3(+)/CD25(+)) cells (P =.009), natural killer (NK; CD56(+)) cells (P =.007), and activated NK (CD56 bright(+)) cells (P: =.039) than those patients mobilized with G-CSF. NK (P =.042) and lymphokine-activated killer (LAK) (P =.016) activity was increased in those mobilized with IL-2 + G-CSF, whereas G-CSF-mobilized patients had a decline in cytolytic activity. In the third week posttransplantation, immune reconstitution was superior in those mobilized with IL-2 plus G-CSF based on greater numbers of activated T cells (P =.003), activated NK cells (P =.04), and greater LAK activity (P =.003). The 16 of 21 IL-2 + G-CSF-mobilized patients with adequate numbers of stem cells (> 1.5 x 10(6) CD34(+) cells/kg) collected engrafted rapidly posttransplantation. CONCLUSION: The results demonstrate that G-CSF + IL-2 can enhance the number and function of antitumor effector cells in a mobilized autograft without impairing the hematologic engraftment, provided that CD34 cell counts are more than 1.5 x 10(6) cells/kg. Mobilization of CD34(+) stem cells does seem to be adversely affected. In those mobilized with IL-2 and G-CSF, post-stem-cell immune reconstitution of antitumor immune effector cells was enhanced.

Daily subcutaneous ultra-low-dose interleukin 2 with daily low-dose interferon-alpha in patients with advanced renal cell carcinoma.

A limited institution Phase II pilot study was performed using a very low-dose combination of daily s.c. interleukin (IL)-2 with IFN-alpha-2b in patients with advanced renal cancer in an attempt to duplicate or increase the response documented with higher dose schedules without the attendant toxicity profile. We selected a dose of IL-2 with documented immunological activity and combined it with clinically active low-dose IFN. Between August 1994 and September 1996, 19 patients with metastatic renal cell carcinoma, who had been judged incapable of tolerating high-dose i.v. IL-2, were treated with IL-2 (1 million units/m2/day) and IFN (1 million units/day), administered s.c. daily. All treatments were administered on an outpatient basis. Virtually all patients had bulky tumor burden with multiple sites of involvement, including five patients with bone metastases. No major objective responses were observed; however, one patient experienced a minor response lasting 13 months, with an associated improvement in performance status. Median survival was 6 months, and 1-year survival was 16%. Toxicity was generally mild and consisted almost entirely of constitutional symptoms. No serious grade 3 or 4 toxicity was observed, although two patients withdrew from treatment due to treatment-related fatigue. On therapy, mild eosinophilia but no lymphocytosis was noted; in fact, peripheral lymphocyte counts decreased, only to rebound after treatment was discontinued. No toxic deaths occurred. Despite the reasonable tolerability of this daily low-dose s.c. regimen, we conclude that this regimen is an ineffective treatment in metastatic renal cell carcinoma patients who are incapable of tolerating high-dose i.v. IL-2.

A phase II trial of interleukin-2 in myelodysplastic syndromes.

Patients with myelodysplastic syndromes (MDS) show a decrease in the number and function of natural killer (NK) cells, including lymphokine activated killer (LAK) cell activity. Interleukin-2 (IL-2) stimulates the proliferation and activity of these lymphocytes. Anecdotal clinical experience has shown haematological and cytogenetic improvement in myelodysplasia by low-dose IL-2 treatment. A total of 10 patients with MDS were treated with 1 million units of IL-2 subcutaneously daily for 12 weeks. Even though improvement in CD16+/CD56+ cell numbers was seen in a majority of the patients, the haematological status and transfusion requirements remained unchanged. There was minimal toxicity from this therapy.