Prolonged follow-up after initial therapy with 2-chlorodeoxyadenosine in patients with indolent non-Hodgkin lymphoma: results of Cancer and Leukemia Group B Study 9153.

BACKGROUND: The objective of this study was to determine the efficacy and toxicity of 2-chlorodeoxyadenosine (2-CdA) in patients with untreated, indolent non-Hodgkin lymphoma (NHL). METHODS: For this multicenter, single-arm, Phase II study, 44 patients with treatment-naive, stage III or IV, indolent NHL (International Working Formulation subtypes A, B, and C) were enrolled. Patients received 0.14 mg/kg per day of 2-CdA as a 2-hour bolus infusion for 5 consecutive days every 28 days until maximal response or a total of 6 cycles. RESULTS: Thirty-eight patients were eligible for response evaluation. The overall response rate was 100% (95% confidence interval [95% CI], 90.8-100%), and the complete response rate was 31.6% (95% CI, 17.5-48.7%). In the intent-to-treat population, the median failure-free survival was 2.0 years (95% CI, 1.3-3.4 years), and the overall survival rate was 7.0 years (95% CI, 4.3-9.4 years). Six patients had sustained remissions that lasted a median of 8.7 years (range, from 5.9 years to > or =11 years). Although 68% of patients experienced at least 1 grade 3 or 4 event, consisting primarily of myelosuppression, severe infections were rare, with only 8 grade 3 infections. Four late malignancies (prostate adenocarcinoma, ductal carcinoma in situ, and myelodysplasia) and 4 patients with large cell transformation were reported. CONCLUSIONS: 2-CdA is an active, well-tolerated therapy for patients with untreated, indolent NHL.

Enhanced survival associated with vitiligo expression during maintenance biotherapy for metastatic melanoma.

Vitiligo, an autoimmune skin disorder, was evaluated in 49 metastatic melanoma patients treated with an immunotherapy regimen of maintenance biotherapy (mBT) following induction concurrent biochemotherapy (cBCT). Patients receiving mBT demonstrated a stable or better response to cBCT. The mBT regimen consisted of outpatient subcutaneous injections of low-dose IL-2 (1 MIU/m(2)) 5/7 days weekly, GM-CSF (125 mcg/m(2)) 14 days monthly, and high-dose pulses of in-patient continuous infusion decrescendo IL-2 (54 MIU/m(2)) over 48 hours monthly for the first 6 months and every 2 months thereafter. The majority of patients had poor prognostic features. Forty-nine patients were without evidence of vitiligo at the start of mBT. Of these, 21 patients (43%) developed vitiligo during mBT and had a median overall survival from the start of mBT of 18.2 months (95% CI, 12.3-N/A) compared to 8.5 months (95%CI <6.7-12.7) for 28 non-vitiligo patients (P=0.027). Six of 21 vitiligo patients (29%) expressed IgG antibody titers to tyrosinase-related protein-2 compared to four of 28 non-vitiligo patients (14%) (P=NS). The development of vitiligo in metastatic melanoma patients on cBCT/mBT immunotherapy correlates with a better therapeutic outcome.

Apoptosis, Bcl-2 antisense, and cancer therapy.

Apoptosis, or programmed cell death, is a complex process of cell turnover involved in both normal and pathologic processes in the body. Impairments in the apoptotic pathways contribute to tumorigenesis and the development of tumor resistance to chemotherapy. The proto-oncogene bcl-2 appears to serve a critical antiapoptotic function. Its broad expression in tumors coupled with its role in resistance to chemotherapy-induced apoptosis make bcl-2 a rational target for anticancer therapy. The Bcl-2 antisense drug oblimersen sodium (Genasense) enhances apoptosis alone and in combination with cytotoxic chemotherapy in vitro and in numerous xenograft models of solid tumors and hematologic cancers. Results from xenograft models of melanoma were especially encouraging, prompting melanoma to be identified as an initial human trial candidate. In a phase II trial in patients with advanced malignant melanoma resistant to first-line chemotherapy (including dacarbazine [DTIC-Dome]), three objective responses and three minor responses to oblimersen plus dacarbazine were observed among 14 patients. In a large randomized phase III trial, oblimersen plus dacarbazine showed a near doubling of response rate vs dacarbazine alone and a significant prolongation of progression-free survival. For the primary endpoint of overall survival, a significant benefit for the combination was not seen. The ability of oblimersen to modulate apoptosis suggests a new paradigm of anticancer therapy that has clinical potential in a variety of solid tumors and hematologic malignancies. Further, oblimersen is the first antisense molecule studied in clinical trials for its anticancer properties, opening up an entirely new direction for therapy.