Strong Activity Shown for Ofatumumab in Refractory CLL
Salvage therapy in chronic lymphocytic leukemia patients who are refractory to both fludarabine and alemtuzumab(Drug information on alemtuzumab) (Campath) or who have bulky fludarabine-refractory disease is of limited benefit, with overall response rates of just 20% to 26% to various approaches. Clearly, this is a setting of great need, and I believe that the new anti-CD20 monoclonal antibody ofatumumab may address this gap nicely. Based on the activity of this drug in early studies, the US Food and Drug Administration (FDA) has accepted the Biologics License Application for ofatumumab, granting it the priority review status of orphan drug designation for the treatment of CLL. If approved, which is more likely than not, ofatumumab would be the first anti-CD20 monoclonal antibody available to treat CLL pts whose disease is resistant to previous therapies. It is currently being studied in a number of combinations, similar to the way we are using rituximab(Drug information on rituximab), and the challenge is to distinguish its benefits from those of rituximab.
The planned interim analysis in the ASCO study by Wierda et al (abstract 7044) is encouraging, showing an ORR of 58% in the whole cohort and 74% in patients with double-refractory disease. We saw that patients who had received all our available agents still responded to this agent. Median progression-free survival surpassed 1 year. It appears that ofatumumab may be effective in individuals with previous rituximab exposure, showing an ORR in that group of 54%, though it is not yet clear whether the difference between rituximab and ofatumumab efficacy is just a dose effect. We will need to determine exactly what this agent can add above and beyond treatment with rituximab. Theoretically, it could compete with rituximab as a treatment in these patients, and in vitro it appears more active. Will it be used just in those patients who are clearly refractory to rituximab? These are critical issues for further study.
Novel HDAC/DAC Inhibitor Is Promising in CTCL
Romidepsin is a pan-HDAC/DAC inhibitor with pleiotropic downstream effects. Phase I studies showed activity in T-cell lymphoma, and two phase II studies confirmed its efficacy and tolerability in the treatment of CTCL. The international study by Demierre and colleagues (abstract 8546) was a pooled analysis of these two trials totaling 167 patients with CTCL (mycosis fungoides or Sézary syndrome), mostly with stage IIB–IV disease, who had progressed on previous treatment with chemotherapy, oral bexarotene (Targretin) or denileukin diftitox (Ontak). As a single agent romidepsin was quite active in CTCL, with an overall response rate of 41% in the evaluable patients (those who received ≥ 2 doses in 2 consecutive cycles), and 42% in patients with advanced-stage disease. These responses were quite durable as well, with a median duration of nearly 15 months.
Importantly, this novel agent provided symptomatic relief from pruritus, which is seen in a significant number of patients, depending on disease CTCL subtype. Here, in a subset of 52 patients with moderate to severe pruritus at baseline, 63% reported some relief, defined as a decrease in the Visual Analog Scale score ≥ 30 mm. This symptomatic relief occurred in the absence of steroids and antihistamines, which were excluded from use in the study. This additional finding verifies the drug’s activity. The FDA has accepted and is reviewing the New Drug Application (NDA) for the use of romidepsin in patients with CTCL, and I predict we can look forward to incorporating this agent into CTCL management.
Bortezomib–Resistant MM Patients Respond to Carfilzomib
For the treatment of bortezomib(Drug information on bortezomib)-resistant MM patients, encouraging activity has been shown with carfilzomib, a novel proteasome inhibitor of the epoxyketone class. Based on its high level of proteasome selectivity and antitumor activity, Jagannath et al (abstract 8504) studied carfilzomib in a multicenter open-label study of 46 heavily pretreated MM patients who had progressed after treatment with all available therapies. With carfilzomib, the clinical benefit rate was 26%, and median progression-free survival was 5 months. About a quarter of patients were able to complete 12 cycles of treatment. While this novel agent appears to have activity in refractory MM, the question is whether it will be less toxic and therefore might replace bortezomib in certain settings. We clearly need an agent that will be as efficacious as bortezomib and at least as effective. This is a disease in which in spite of our best treatments, only a minority of patients have prolonged survival.
Idiotype vaccine therapy (BiovaxID) in follicular lymphoma in first complete remission: Phase III clinical trial results
S.J. Schuster et al
Complete remissions with weekly dosing of SGN-35, a novel antibody-drug conjugate targeting CD30, in a phase I dose-escalation study in patients with relapsed or refractory Hodgkin lymphoma or systemic anaplastic large cell lymphoma
N. Bartlett et al
Activity of ofatumumab, a novel CD20 mAb, and prior rituximab exposure in patients with fludarabine- and alemtuzumab-refractory or bulky fludarabine-refractory chronic lymphocytic leukemia
W.G. Wierda et al
Pooled analyses of two international, multicenter clinical studies of romidepsin in 167 patients with cutaneous T-cell lymphoma (CTCL)
M. Demierre et al
Final results of PX-171-003-A0, part 1 of an open-label, single-arm, phase II study of carfilzomib in patients with relapsed and refractory multiple myeloma
S. Jagannath et al