Management of Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia

Farhad Ravandi-Kashani, MD

As part of our coverage of the American Society of Hematology (ASH) Annual Meeting & Exposition held December 9–12 in Atlanta, we are speaking with Farhad Ravandi-Kashani, MD, professor of medicine and the chief of the section of developmental therapeutics in the department of leukemia at MD Anderson Cancer Center in Houston, about the management of patients with Philadelphia chromosome–positive acute lymphoblastic leukemia (ALL). Dr. Ravandi-Kashani will lead a discussion titled, “Current Management of Philadelphia Chromosome–Positive ALL and the Role of Stem Cell Transplantation” during an education session at the meeting.

-Interviewed by Anna Azvolinsky  

Cancer Network: First, what percentage of all ALL patients are positive for the Philadelphia chromosome and what does that mean in terms of the biology of this subtype compared with other subtypes of ALL?

Dr. Ravandi-Kashani: The Philadelphia chromosome was originally described in chronic myeloid leukemia and is a translocation between chromosomes 9 and 22 that occurs in different percentages of patients with ALL depending on their age. It is fairly uncommon in children with ALL, only accounting for about 5% of patients. But in the adult population it accounts for about 25%; this proportion increases in the elderly, approaching as high as 40% or 45%. In terms of biology, this used to be one of the most difficult subtypes of ALL to treat with traditional ALL combination chemotherapy regimens. Prior to the introduction of tyrosine kinase inhibitors (TKIs), the literature always showed that the median survival with chemotherapy-based regimens was certainly less than 1 year and perhaps even shorter. The proportion of patients alive at 2 to 3 years was only about 15% to 20%, and perhaps a bit higher in the childhood population, but the majority of the patients who were alive longer term were those who were able to undergo an allogeneic stem cell transplant. Clearly, the introduction of TKIs has made a difference and has significantly improved the outcomes for both children and adults.

Cancer Network: You already mentioned TKIs; can you talk about the options for patients who are newly diagnosed? Are the TKIs the mainstay of initial treatment for this subtype of ALL?

Dr. Ravandi-Kashani: In my opinion, and I believe in the opinion of most physicians who treat this disease, the TKIs should be a part of the initial treatment in all patients, including children, adults, and the elderly. Now, there is some debate about whether these agents should be used as monotherapy or with minimal additional therapy, particularly in the older adult population, in the very elderly, or whether they should be combined with chemotherapy. I think there are a number of studies that have looked at this and have come up with somewhat different conclusions. However, I think the conclusion is unified-that in a younger patient who can tolerate the addition of ALL-type chemotherapy, that addition of chemotherapy to TKIs does improve the response, mainly the molecular response. However, in the older populations, in the elderly, there can be some argument for limiting traditional chemotherapy and just using TKI monotherapy because of the toxicity associated with chemotherapy. For example, the Italian groups have been conducting a number of studies using TKI monotherapy initially with imatinib, with dasatinib, and more recently with ponatinib, which have shown that you can actually achieve almost universal complete response with a TKI monotherapy plus some additional steroids. This is obviously very important because, again, in the older population, you are eliminating toxicity and early induction death.

Unfortunately, such a strategy does not lead to a long-term cure and long-term survival, and we certainly need to consolidate these remissions with additional therapy, whatever it may be-in the younger patients it can be the combination of chemotherapy and a TKI or allogeneic stem cell transplant or autologous stem cell transplant. In the older patients, it is best to perhaps reduce the chemotherapy and some of the newer agents that are becoming available. So, to answer your question, TKIs are definitely part of the initial treatment, but the form they take may depend on the age of the patient, and to some degree, on the desire to do an allogeneic transplant. Even in the younger patients, some experts suggest that you use minimal or no chemotherapy plus a TKI and then do an allogeneic stem cell transplant. That is a reasonable approach, but there could be a day when we completely eliminate stem cell transplants in these patients.

Cancer Network: In regard to stem cell transplantation, where does the transplant fit into the course of therapy, and for which patients is it appropriate?

Dr. Ravandi-Kashani: As I mentioned, prior to the introduction of TKIs, without an allogeneic stem cell transplant, it would be extremely unlikely that you would achieve a long-term cure in Philadelphia chromosome–positive ALL. Allogeneic stem cell transplant has been considered standard therapy in first remission in all patients with Philadelphia chromosome–positive ALL who have a donor and are able to undergo transplantation. Also, as I mentioned, a lot of the patients with Philadelphia chromosome–positive ALL are older patients, people over the age of 60 and sometimes 65 and 70. Although there have been improvements in transplantation and there are now non-myeloablative regimens available, experts would agree that mortality and morbidity of transplant goes up significantly as the patient age increases. There have been attempts by some groups such as ours to try to see if we can actually do away with transplant initially, at least in some populations like the older patients or less fit patients, and if it is feasible, perhaps to even think about doing away with transplant in all patients. Even in the very young, there are still mortality and morbidity risks associated with transplant.

There are now very useful tools that can help us to achieve this. First, there are TKIs, which are very active; more importantly the newer third-generation TKIs are extremely potent and are active against resistance-inducing mutations such as T315I. Second, there are now agents that are becoming available such as monoclonal antibody–based therapies. We have shown that with the combination of chemotherapy and TKIs, there is a subset of patients who are cured without undergoing allogeneic stem cell transplant in first remission. Third, we now have surrogate markers specifically for minimal residual disease and molecular testing for the signature BCR-ABL translocation products, which can help us understand if the patient has achieved good enough remission that is unlikely to be associated with future relapse. Again, there have been many studies that have shown that achieving a complete molecular remission is certainly associated with a much higher likelihood of relapse-free and overall survival even without an allogeneic stem cell transplant. Overall, there is now an increased availability of effective tools for this disease, as well as better ways of monitoring for adequate therapy, specifically for eradication of minimal residual disease, that can hopefully allow us in the future to confidently decide that the patient does not need a transplant or that the patient is likely to relapse and we should consider transplant in first remission.

Cancer Network: Thank you so much for joining us today, Dr. Ravandi-Kashani, and enjoy the conference.

Dr. Ravandi-Kashani: Thank you very much.