BTK INHIBITORS-A BREAKTHROUGH FOR LYMPHOMA TREATMENT 

Hello. This is Bruce Cheson from Georgetown University Hospital and the Lombardi Comprehensive Cancer Center, speaking to you for Medscape Hematology.

When I gave talks with Kodachrome slides many years ago, I had a slide that said, "More isn't better; different is better." I think that was the critical message from the American Society of Hematology (ASH) meeting [in Atlanta, Georgia, in December 2012]. New chemotherapy drugs are no longer in development, but rather, new strategies to minimize therapy in some regards and to get rid of chemotherapy in other regards are now on a roll.

Let's look at the RAPID trial, which was presented by John Radford.^[1] The RAPID trial used a risk-adapted approach to attempt to reduce the amount of treatment for patients with Hodgkin lymphoma. Patients received 3 cycles of ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) therapy and then underwent PET scan. If the PET was positive, patients received a fourth cycle, followed by involved-field radiation. If the PET scan was negative, they were randomized to receive no more chemotherapy -- no more therapy -- or to receive involved-field radiation.

This was a noninferiority study, and the investigators accrued 602 patients with early-stage Hodgkin lymphoma. About two thirds were favorable according to either European Organisation for Research and Treatment of Cancer (EORTC) or German criteria.

These investigators found that indeed, you could omit the radiation therapy safely in this patient population, on the basis of the noninferiority design of the study. Of the patients who were PET-negative and received involved-field radiation, 93% were alive without disease, compared with 90% who had no further therapy. Pretty close.

I think these data support the possibility that you can give only 3 cycles of therapy in these favorable patients, and they will do just fine with no further treatment. Again, we need to see the final analyses -- longer-term follow-up for toxicities and for late relapses -- but there you go.

More critical were studies that showed that you could perhaps get away from chemotherapy altogether. In a study of patients with acute promyelocytic leukemia (APL),^[2] participants were randomly assigned to receive chemotherapy or a combination of tretinoin (all-trans retinoic acid, or ATRA) and arsenic. These were low-risk patients, with less than 10,000 white blood cells at presentation. The outcomes were at least as good in the patients who did not receive chemotherapy. That is a whole new horizon. Imagine treating acute leukemia without chemotherapy.

Next [at ASH] came studies^[3,4] showing us promising new agents: the kinases that are downstream from the B-cell receptor, those that interfere with Bruton tyrosine kinase or PI-3 (phosphoinositide-3) kinase -- for example, the drugs ibrutinib and idelalisib, respectively.

The results were extraordinary. Approximately 40% of patients with the ABC subtype of diffuse large B-cell lymphoma who had relapsed or were refractory to treatment responded to ibrutinib.^[3] It does not seem to work in patients with the GCB subtype, but we need more numbers to look at that. We were seeing response rates of over 60% with that drug in relapsed or refractory patients with refractory mantle cell lymphoma, as well as complete remission rates like nothing we have seen with any other drug in this context.^[4] Of patients with chronic lymphocytic leukemia, who had relapsed after previous therapy, or who were previously untreated, more than 70% were responding.^[5] Even the patients with 17p deletion have a very high response rate to such drugs as ibrutinib, and these responses seem to be durable.^[5] Follow-up is not very long, but response may last even for a couple of years.

Other drugs are in development: ABT-199, a Bcl-2 inhibitor with exciting results,^[6] and IPI-145, a PI-3 kinase delta-gamma combined inhibitor, with preliminary results suggesting activity in B-cell and also in T-cell lymphoma.^[7]

I came away from the ASH meeting feeling enthusiastic that the world is changing. Clearly, we now will be hearing a lot about targeted therapies. Hopefully, we will get to a point where we can combine these targeted therapies. If we can do this in a rational manner in the right patient population, I think some of these approaches may cure diseases that have been incurable to date. And if not cured, aggressive diseases -- indolent, incurable diseases -- may be transformed into chronic diseases for which a patient takes 1 or 2 pills a day and does just fine. These are very exciting times.

This is Bruce Cheson, signing off for Medscape Hematology. I look forward to speaking with you again in the near future. Have a great day.