Azacitidine extends overall survival in higher-risk myelodysplastic syndrome (MDS) without the necessity for complete remission.

The outcome of MDS for those receiving supportive care can be predicted based on the International Prognostic Scoring System (IPSS) and includes the median survival and the percent of patients who develop leukemia. The goals of therapy have been to improve quality of life, control symptoms, and delay or decrease the progression to acute leukemia while improving survival. Three drugs have US Food and Drug Administration (FDA) approval for the treatment of MDS: 5-azacitidine, decitabine, and lenalidomide. For patients with higher-risk MDS, the International Working Group (IWG) 2000 response criteria suggested that a complete response (CR) was necessary to extend overall survival (OS). Fenaux et al presented the results of a phase III survival study (AZA-001) of 5-azacitadine (AZA) vs a conventional care regimen (CCR) at the 2007 American Society of Hematology Annual Meeting and showed an overall survival advantage for AZA in patients with high-risk MDS. List et al investigated the relationship between the best IWG 2000 response and prolongation of OS for patients in the AZA-001 trial. Patients (358) were randomized to AZA 75 mg/m²/day x 7 days every 28 days or CCR including BSC, low-dose ara-C, or induction 7 + 3 chemotherapy. When comparing responses of AZA vs CCR, it was noted that the overall response rate (ORR) was 29% vs 12%, CR was 17% vs 8%, partial response (PR) 12% vs 4%, stable disease (SD) 42% vs 39%, and hematologic improvement major + minor (HI) was 49% vs 29%. One-year survival rates were superior for AZA for the overall trial and for patients with a CR, but also for those patients who achieved a best response of HI. This trial suggests that even with agents with a low CR rate, the attainment of a CR is not necessary to prolong survival and that perhaps all patients with MDS should be offered therapy.

Dasatinib 2-year efficacy in patients with chronic-phase (CP) CML with resistance or intolerance to imatinib (START-C)

Mauro et al presented a 2-year follow-up of the phase II study in 387 patients with CML-CP using a starting dose of dasatinib 70 mg twice per day (BID) with dose escalations allowed for lack of response and dose reductions for toxicity. The primary endpoint was a major cytogenetic response rate (MCyR). After a minimal follow-up of 2 years, complete hematologic response was seen in 91%, MCyR in 62%, complete cytogenetic response rate (CCyR) in 53%, and major molecular response (MMR) in 47% of patients. Progression-free survival (PFS) was 80%, and OS 94% at 24 months. Dose limiting toxicities included neutropenia and thrombocytopenia and pleural effusions. Abstract 7009.

Nilotinib in patients with imatinib-resistant or -intolerant CML-CP: Updated phase II results.

Kantarjian et al presented an update of a phase II trial using nilotinib in 321 patients with imatinib-resistant or intolerant Philadelphia chromosome-positive (Ph+) CML-CP. Nilotinib was administered at a dose of 400 mg BID with escalation up to 600 mg BID for poor response. Major cytogenetic response was seen in 55% of 227 imatinib-resistant patients and 63% of the imatinib-intolerant patients. Eighty-four percent of patients maintained a MCyR for at least 18 months. Dose-limiting toxicity was myelosuppression. Abstract 7010.

Bosutinib is safe and active in patients with CML-CP with resistance or intolerance to imatinib and other TKIs.

Bruemmendorf et al reported on 152 patients with CML-CP post–imatinib resistance or intolerance, but with only a median of 5 months of follow-up. Responses were seen in a high proportion of patients and dose-limiting toxicity was rash and liver enzyme elevation. Abstract 7001.

Safety and efficacy of lenalidomide (Len), bortezomib (Bz), and dexamethasone (Dex) in patients with newly diagnosed multiple myeloma: A phase I/II study

Bortezomib as a single agent and Len + Dex are approved treatments for patients with relapsed multiple myeloma who have received prior therapy. Trials have also shown that Bz/Dex and Len/Dex are active in front-line multiple myeloma. A study from Richardson et al evaluated the efficacy of Len/Bz/Dex in the front-line setting. Patients received Bz day 1, Dex days 1 and 2, and Len daily for up to eight 21-day cycles. Best response in 66 evaluable patients was CR 26%, near complete response (nCR) 11%, very good partial response (VGPR) 35%, PR 27%, and minimal response (MR) 2%. Overall response rate was 98%, with the CR/nCR 36%. The toxicities were manageable with <10% myelosuppression, hypophosphatemia, and deep vein thrombosis (DVT). It was noted that the combination did not adversely affect stem cell harvesting and the transplant course has been unremarkable in patients proceeding to stem cell transplantation. Abstract 8520.

Axitinib (AG-013736) in patients with metastatic melanoma: a phase II study.

Metastatic melanoma has significant resistance to standard chemotherapy agents with the response rate of temozolomide being only 14%, PFS 1.9 months, and OS 7.7 months. It has been noted that increased serum VEGF is associated with poor survival in patients with melanoma. Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptor (VEGFR) 1, 2, and 3. Fruehauf et al presented the results of a phase II trial of axitinib at 5 mg BID. Patients had metastatic melanoma and could have had no more than one prior therapy for metastatic disease. The ORR was 19% with an additional 28% of patients having stable disease for ≥16 weeks. Common treatment-related adverse events (AEs ) were fatigue, hypertension, proteinuria, hoarseness, and diarrhea. An unplanned subgroup analysis of having at least one diastolic BP measurement ≥ 90 revealed a median OS of 13 months with hypertension and 6.4 months for those with no diastolic hypertension. Axitinib appears to be a very promising agent for metastatic melanoma. Abstract 9006.

Phase II trial of combination thalidomide plus temozolomide in patients with metastatic malignant melanoma: SWOG S0508.

Small single institution phase II trials have suggested promising response rates with the combination of temozolomide and thalidomide in the treatment of malignant melanoma. This SWOG cooperative group trial was performed to assess response and toxicity of this regimen. Sixty-four patients with metastatic cutaneous malignant melanoma with up to one prior systemic therapy for melanoma were enrolled. Patients received thalidomide combined with temozolomide at a dose of 75 mg/m²/day for 6 weeks followed by a 2 week break. The dose of thalidomide was different depending upon age. For patients aged <70 years, 200 mg was the starting does titrated to a maximum of 400 mg/day. For patients aged >70 years, 100 mg was the starting dose, titrated to a maximum of 250 mg/day. The response rate was 13% with a 6-month PFS of 15% and 1-year OS of 35%. However, when compared with a meta-analysis on systemic therapy of melanoma, this combination fares no better than 70 negative phase II trials. The authors stated that this regimen should not be considered a standard treatment for metastatic melanoma. Abstract 9007.

Although the June 2008 OncoFacts and this August 2008 edition review some of the highlights of the ASCO 2008 meeting, they pale in comparison to the very comprehensive reviews that have been delivered as part of the Imedex 2008 Oncology Highlight^SM meetings. Two meetings are still available over the weekends of August 2 and August 9 in New York City, and Aventura, Florida, respectively. In addition, online materials including a Webcast and online monograph will become available based on these meetings. So, if you are unable to personally attend, look for more information in the future on the Imedex Website.

The next issue of OncoFacts™ will be in September 2008 and then monthly throughout the year.

OncoFacts™ Editor:

Christy Russell, MD

For ongoing improvement, we would appreciate your comments and suggestions. Email your suggestions to: elearning@imedex.com

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