BW Bill Wierda
IV Welcome to e-Cancer TV here at the American Society of Haematology meeting. Bill Wierda, you’re with us now to talk about a fascinating topic because chronic lymphocytic leukaemia is not an easy disease to treat. What are the categories or patients that you’ve been looking at?
BW Specifically related to the abstract that I’m presenting at this meeting, this is a population of patients who’ve failed and are refractory to standard therapies. So there are two groups of patients in this analysis – one, is patients that are refractory or resistant to Fludarabine and Campath, and second group are patients who are refractory to Fludarabine and who have bulky lymph nodes, greater than five centimetres. So that second category is a patient population where we wouldn’t expect a significant response rate with Alemtuzumab mono therapy, and so those are two parallel groups that were enrolled and treated on this study of a single agent monoclonal antibody against CD20.
IV And how do you define refractory to Fludarabine?
BW There is a standard definition for refractory Fludarabine, as well as refractory to Alemtuzumab. So refractory to Fludarabine is failure to achieve at least a partial remission or better, with the last Fludarabine based treatment – and in this study they had to receive at least two cycle of Fludarabine based treatment – or relapse in progression within six months of their last Fludarabine based therapy – so that’s Fludarabine refractory. Alemtuzumab is similar in that patients have... refractory patients fail to achieve at least a partial remission with their last Alemtuzumab based regimen, or relapse in progression within six months.
IV And you’ve also got the bulky lymphadenopathy?
BW The bulky lymphadenopathy, again, are patients who we don’t expect to have a significant response rate with Alemtuzumab or Campath mono therapy.
IV So these patients are running out of options, enter a new monoclonal...
BW Correct. So these patients are historically a population who have very, very few treatment choices, and we did an analysis at the MD Anderson of patients with similar characteristic, and overall their response rate to a variety of different treatments that we gave them was about 20%; 20% to 26%, and their survival was about eight months – so they have a very short survival in relation to patients with this disease and are very high risk.
IV So in the study with Alemtuzumab you are effectively going against historically controls?
IV Could you tell me about the study?
BW So the study again is a multi centre study, it was involving US and European sites. There are two cohorts of patients on the study, patients who were refractory to both Fludarabine and Campath, and patients who were refractory to Fludarabine with bulky lymphadenopathy. And patients receive a total of 12 doses of Ofatumumab as mono therapy – they’re given a 300 milligram dose for the first dose, and then weekly doses for seven additional doses at 2 grams flat dose, and then four monthly doses of 2 grams.
IV Now, on the early results you got approval from the FDA?
BW We got approval from the FDA for Ofatumumab in patients who were double refractory; the double refractory group was the group that was approved by the FDA and the EMEA for marketing of Ofatumumab, but we did not get approval for the bulky Fludarabine refractory group.
IV So what was the news now from Ash here?
BW The bottom line from this analysis is that the results from the final analysis and over 200 patients enrolled on this study, the response rate was consistent – so a roughly 50% response rate. The response rate that we were trying to beat was 15%, so this was significantly higher than our historic baseline or our historic control that we were trying to achieve. So the results with this analysis are consistent with the interim analysis that we reported a couple of years ago, and we have greater patient numbers. We’re now able to do some sub group analysis to determine which patients may benefit more or less than others with Ofatumumab mono therapy.
IV So what’s the message coming out of this for the practical cancer doctor with a patient that he wants to give some sort of salvage therapy to, with chronic lymphocytic leukaemia?
BW I think there’s a couple of messages. One, is that it’s an active drug, an active antibody as mono therapy, and we haven’t seen that as much with Rituximab; Rituximab is a very effective antibody if you use it in combination with chemotherapy. This trial demonstrates activity although we use a significantly higher amount of drug, nevertheless we see significant activity with mono therapy with Ofatumumab. We see... the toxicity profile is a very safe toxicity profile, we didn’t see any unexpected toxicity or side effects or reactions with the drug. This is a heavily pre-treated population so they’re at very high risk for infection, so we did see some infectious complications that probably are more a reflection of the patient population than the drug itself. Those are the two major conclusions.
IV There are indeed some adverse events, but as you say, relatively low grade? Easily manageable?
BW So the major side effect was infusion related reactions which we see with other antibodies, including Rituximab – fever, sweats, sometimes shortness of breath that occur during the infusion. In this study those were all either grade one or grade two, and resolved when the infusions were completed, and subsided as patients continued with their treatment.
IV You did have some early deaths and some fatal infections.
IV On balance are you saving life, do you think?
BW I think that we are; so we did a landmark... what’s called a landmark analysis where we do an analysis of survival for patients who reach a certain point during the trial. So the landmark analysis that we did was we did an analysis for survival for patients who reached the 12 week time point, and with that analysis we showed that patients who respond to treatment have an improved survival over those patients who were not responding to treatment. This is not a direct demonstration of improvement in survival, but in terms of the data that we have it’s clearly an indication of improvement in survival with treatment with this drug.
IV What is this telling us about CLL, not only for the patients who need salvage therapy, but also perhaps for treatment of earlier stages of this very common disease?
BW Well, we’re still sticking to the NCI working group criteria that we used to determine when patients should start on treatment. I don’t think that this trial itself will change that strategy or approach, so we’re still going to use the NCI working group or IWCL working group criteria as to when to start treatment. There are a lot of studies that are ongoing now with Ofatumumab; I have a study that will be opening soon for early intervention to try to delay time to chemotherapy. So we’ve developed a model where we can identify patients at high risk for needing treatment, and we’re treating those patients with Ofatumumab early to try to determine if we can delay their need for chemotherapy. So there are a lot of strategies and things that are being studied right now with Ofatumumab and trying to improve the outcomes for patients with this disease.
IV So what might be the clinical implications or potential clinical implications that you’d like to put in the minds of busy doctors now?
BW I think that this is a safe drug, it’s an active drug. I think that clearly the data indicates improvement in outcomes, it’s a well tolerated treatment for patients who have refractory disease, and therefore now we have another option... or another option or tool to use to treat those patients who are refractory or resistant to standard therapies.
IV Bill, it’s great to have you with us. Thank you for taking part in e-Cancer TV.
BW Thank you.