One-Two Punch for Leukemia -- Full-Length Doctor's Interview

Ivanhoe Broadcast News Interview with
John Roberts, M.D., Medical Oncologist,
Professor of Internal Medicine in the Division of Hematology/Oncology,
Virginia Commonwealth University, Richmond, Virginia
TOPIC: One-Two Punch for Leukemia

What is the difference between the different kinds of leukemia?

Dr. Roberts: There are basically four kinds of leukemias. There are acute leukemias, which progress rapidly and lead to death in a period of time, measured in weeks or months, unless there's an effective treatment. And there are chronic leukemias, which progress slowly and even without treatment, may allow people to live for months or years, but will eventually lead to death if an effective treatment is not identified.

And the difference between myelogenous and lymphocytic leukemias?

Dr. Roberts: Then there are two types of white blood cells. There are granulocytes, which are infection-fighting cells, and then there are lymphocytes, which are cells involved in the immune system. So you can have an acute leukemia of the lymphocytes, or a chronic leukemia of the lymphocytes, and one can have an acute leukemia of the granulocytes, or a chronic leukemia of the granulocytes, also called, myelogenous leukemia.

Before bryostatin, how would chronic lymphocytic leukemia traditionally have been treated once it reached the point of needing attention?

Dr. Roberts: The standard treatment of chronic lymphocytic leukemia is with chemotherapy or cytotoxic agents. For many years, the standard drug was a drug called chlorambucil. In the early 90s a new group of drugs was developed. And when we started this study in the late 90s it was unclear whether fludarabine or chlorambucil was the preferred treatment for chronic lymphocytic leukemia. Both fludarabine and chlorambucil are drugs that work by killing cancer cells, and there is collateral damage where they kill other normal cells. So, there are risks and side effects associated with both of these treatments.

Bryostatin represents a new approach, in that we're trying to identify drugs which specifically target the cancer cell, which exploit biological differences between cancer cells and normal cells. So that hopefully we can do a good job of treating the disease without causing as many side effects or long term problems in patients with cancer. In this particular study, we've combined bryostatin with a standard chemotherapy drug, in this case, fludarabine, with the expectation, based upon laboratory studies, that the combination would be more effective than fludarabine alone, and probably not more toxic.

I think our results to date suggest that it's not more toxic than fludarabine alone. We have seen promising responses in patients treated to date. It will require more research to see whether the combination of bryostatin and fludarabine becomes a standard treatment in the future.

Have you been able to use less of the toxic fludarabine since it's been combined with the bryostatin?

Dr. Roberts: For scientific reasons, we've increased the dose of both drugs so that patients being treated now are being treated at standard doses of fludarabine and moderated doses of bryostatin. We still think, in general, for cytotoxic drugs, that the highest dose that we can give is the dose that's most likely to be effective. So for fludarabine, our thought would be that the highest dose, is the best dose. For bryostatin, it's a little unclear. One of the issues we'll have to grapple with as we pursue further research in this area, is trying to sort out what the best dose of bryostatin might be, and how we would recognize it.

Are patients still dealing with the same type of side effects with this combination treatment? Is there a difference in the side effects from when they were being treated on fludarabine alone?

Dr. Roberts: The goal in this study is to improve the treatment outcome. For many patients with CLL, although therapies available to date are not curative, we can control the disease for quite some time. Another group of patients in these studies are patients with non-Hodgkin's lymphomas, also called indolent non-Hodgkin's lymphomas. These are diseases that commonly affect people in mid life, and are diseases that are responsive to chemotherapy, but rarely, if ever, cured with chemotherapy -- at least chemotherapy in standard doses. One of our hopes with this approach is that we might identify a treatment that is potentially curative for non-Hodgkin's lymphomas, with the combination of fludarabine and bryostatin. Of course that's speculation; we haven't demonstrated that to date.

What class of drugs is bryostatin a member of?

Dr. Roberts: Whereas fludarabine would be considered a cytotoxic agent, a drug that directly kills cancer cells, I'd classify bryostatin as a biologic response modifier. That is, it's a drug that changes the biology of the cancer cell so that it responds differently to things that it encounters in its environment, like fludarabine.

What it is that the combination treatment including bryostatin does differently than traditional therapy?

Dr. Roberts: The fludarabine injures cancer cells by making it difficult for them to reproduce their DNA. Since cancer cells are dividing, each time they divide, they need to reproduce the DNA so that each daughter cell has a full compliment of DNA. Fludarabine interferes with the process from a biochemical standpoint. When cells are operating under stress, like chemotherapy-induced stress, there are a number of biological responses that are brought into play. We think that bryostatin changes the balance of those biological responses to the injury induced by the fludarabine. So that the cells, instead of trying to divide and go on, sort of give up the ghost and go into what we call a program cell death pathway or amitosis, where the cells actually terminate themselves.

Fludarabine directly injures cancer cells as well as normal cells. If the injury is sufficient, the cancer cells die. Bryostatin, we think, modulates or changes the response of the cancer cells to that injury, so that they are more likely to die as a response to the injury induced by the chemotherapy drugs.

So with a minor injury, they commit suicide?

Dr. Roberts: That's right, yeah. One of the new discoveries in cancer research in the last 10 or 15 years, is that many times cancer cells decide to, in a sense, commit suicide. They go through a process of cell directed death. We think that chemotherapy often works by changing the balance so that cells are more likely to go through this suicide pathway. Our goal with the bryostatin, fludarabine study, is to put cells in a precarious situation with the fludarabine and then make it more likely that, from the precarious situation, they will go on to cell directed suicide. We hope to increase the effectiveness of fludarabine by changing the biological response to fludarabine, from one of trying to survive, to going ahead and dying.

How have the patients in the study been responding?

Dr. Roberts: There are a number of patients who have been treated in this study whose disease has gone into remission and has stayed in remission for many months, or even years off treatment. One of the most interesting and promising outcomes of this study is that we've enrolled in this study patients who previously had been treated with fludarabine as a single drug. Indeed, the tumor had increased while they were on fludarabine treatment. Yet some, not all, but some of these patients, when retreated with fludarabine, but in combination with bryostatin, have undergone significant tumor responses. This suggests to us that adding bryostatin to fludarabine may really make a difference in the treatment of cancer.

What phase study is this?

Dr. Roberts: This is a Phase I study.

So there are no specific results that exist?

Dr. Roberts: That's correct.

In general, is the goal to treat their cancer and at least extend the amount of time before they need treatment again?

Dr. Roberts: For many cancers we don't have curative therapies at this time. A valid research goal is to attempt to identify therapies which either prolong the time that we can control the cancer, or reduce the side effects that patients experience while we're controlling the cancer. A long-term goal of this sort of research, of course, is to develop drug combinations, or other treatment approaches, which will allow us to cure patients, so that they can forget about the cancer, and go on with their lives.

Are you now studying bryostatin for other forms of leukemia as well?

Dr. Roberts: Yes. We have two studies ongoing with the bryostatin and blood malignancies. One is in chronic lymphocytic leukemia and the other is in acute myelogenous leukemia.

Is there anything else you would like to add?

Dr. Roberts: We've been trying to learn how to treat cancer with drugs for about 50 years now. For most of that time, we were working in the dark. We didn't have a fundamental understanding of the difference between cancer cells and normal cells, that allowed us to identify drugs which would selectively kill the cancer cells while sparing the normal cells. In the last 10 or 15 years, we've really developed some fundamental insights into differences between cancer and normal cells. The challenge now is to turn those fundamental insights into the biology of cancer, into new treatments, which really are selective -- which kill cancer cells dead, but at the same time, don't cause serious side effects to normal cells, and don't cause serious side effects to our patients. It's a very exciting time to be working in this field because with this understanding, I think we will develop new, more effective, and better tolerated therapies in the future.

END OF INTERVIEW

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If you would like more information, please contact:

Connie Honeycutt
Clinical Research Nurse Coordinator
Virginia Commonwealth University
401 College Street
PO Box 980037
Richmond, VA 23298
(804) 628-1885
choneyc@hsc.vcu.edu