Reports from ASH - CML (Practical Approaches to the Patient with)< Back to News
Orlando, December 3, 2010 - Every year, the Friday before ASH is a busy day as satellite symposiums kick off prior to the conference. A variety of programs are provided across all blood related disorders. These events are not actually PART of ASH but serve to provide many healthcare professionals and others the opportunity to learn more about these diseases and hear from the key players in the field. They also qualify as Continuing Medical Education (CME) credit for healthcare professionals.
This program, Practical Approaches to the Patient with CML, was no exception. Five of the world’s most recognized CML Specialists, three of which are on our Medical Advisory Board, made up the panel of presenters. That panel was Jorge Cortes, MD, Michael Deininger, MD, PhD, John M. Goldman, MD, Timothy P. Hughes, MD, and Moshe Talpaz, MD.
In an attempt to make this report easier to follow, it is broken into sections.
Part 1 – Pertinent Pathophysiology of CML and Clinical Implications.
The first to present was Dr. Michael Deininger. Dr. Deininger practices at the Huntsman Cancer institute, the University of Utah, Salt Lake City, UT.
To begin the program, Dr. Deininger began by sharing some of the history of leukemias, including some of the early pioneers. A timeline of CML was presented, indicating that the first concept of leukemia, or "white blood" as a disease entity happened in 1845 with the term "leukemia" being established in 1847. In 1865, arsenic was used to treat the disease, and it was not until 1872 that the realization that the disease originated in the bone marrow. 93 years passed before Bisulfan was introduced as a treatment option. A year later, in 1960, the key differentiating discovery of CML, the Philadelphia Chromosome, began to further define this subset of leukemias with which we live.
Dr. Deininger moved next to share with the audience that the key trigger for CML is indeed the exchange of genetic material between chromosomes 9 and 22 (which create the Philadelphia Chromosome). This translocation occurs when a portion of 9 and a portion of 22 (which have broken off their respective chromosomes) fuses together. The Philadelphia Chromosome is actually the gene referred to as BCR - ABL. It is BCR-ABL that initiates the proliferation (over production) of white cells; reduced apoptosis (apoptosis = cell death); and creates additional instabilities in a person’s DNA.
Following this introductory section, Deninger went on to describe how BCR-ABL (the Philadelphia Chromosome) sets off a domino effect by creating additional pathways for the disease to progress. Additionally, some CML cells survive, even in the presence of the drugs we currently use for treatment, the TKIs (Tyrosine Kinase Inhibitors). These “immortal” cells are referred to as “quiescent CML stem cells”. He shared that researchers are realizing that when additional pathways are opened by the creation/activation of BCR-ABL, it is possible that the disease can become independent of this very anomaly that is it’s hallmark.
Ultimately, the take away message of Deininger’s presentation was that BCR-ABL (the Philadelphia Chromosome) is the primary “target” for inhibition by TKIs such as Imatinib, Dasatinib, and Nilotinib, however, downstream pathways may also be useful targets if they are co-activated in concert with BCR-ABL. Additionally, CML stem cells are not “addicted” to, or solely dependent upon BCR-ABL and therefore killing these stem cells (“the mother cells”) will require targeting different disease pathways.
Part 2 – Personalization of Frontline CML Management
Next to present was Dr. Jorge Cortes from M.D. Anderson Cancer Center in Houston, Texas.
Dr. Cortes’ presentation was particularly timely since with the approval of Dasatinib and Nilotinib for frontline therapy, the ability to tailor CML therapy to the individual patient is now possible. As we know from recent study results, these two drugs drive stronger and deeper responses. Additionally, these responses are happening more rapidly following diagnosis, which has been shown to reduce the chance of disease progression in a dramatic way.
Cortes began by sharing the current available therapies for patients, including standard and high-dose Imatinib, Imatinib-based combinations, and Dasatinib and Nilotinib, once only available after Imatinib failure.
With today’s treatment armamentarium, the difficulty physicians and treatment professionals are facing is that of determining WHICH therapy to use to achieve the best results with the least adverse events (side effects, etc). His argument covered all angles of the decision. When considering Imatinib, we know that most patients do well; we have used Imatinib longer and thus have some history upon which to rely; we may not have another option to use if they fail; the other options may not prolong survival beyond that of Imatinib; and the cost difference. All of these must be considered when making the choice. Additionally, each patient’s health history becomes even more important as side effects or drug interactions must be considered across a variety of drugs from the very start. Obviously, when there were fewer options in the frontline setting, the choice was perhaps easier.
To end the session, Dr. Cortes asked participants to consider how they would treat someone. After a short time of contemplation, he then asked them to consider how they would treat someone from their own family. Good food for thought, don’t you think?
Part 3 - Optimal Monitoring of Treatment Response in CML
Dr. Timothy Hughes, University of Adelaide, Adelaide, Australia spoke on monitoring CML and the importance of achieving timely response to therapy.
The value of close monitoring is that it serves to identify suboptimal response during the initial phase of someone’s treatment; to assess the dynamics of leukemic decline and rise by identifying resistance or poor adherence; and to determine the achievement of CMR (Complete Molecular Response) at a 4.5 log reduction in the number of leukemia cells.
CMR or “Complete Molecular Response” is defined as the absence of detectable BCR-ABL in a sample of sufficient quality to ensure the limit of detection is at least 4.5 log below the standardized baseline level. On the international reporting scale, this is below 0.0032%. Dr. Hughes went on to say that according to THIS definition, patients might have negative test results showing undetectable levels of disease, yet they may not have yet achieved CMR. Something to consider is that here in the States there are inconsistencies with labs being on the international scale. Therefore it is important that patients understand that, depending upon the lab utilized, test results may vary greatly from lab to lab. Ultimately, any detectable BCR-ABL indicates lack of CMR (when international scale is used – no other scale can determine CMR).
Response timelines are important to observe because they can provide a chance for physicians to evaluate patients against a standard. In doing so, suboptimal response can be addressed in a timely manner to protect against disease progression and to determine if dose escalation might be indicated.
Achievement of CMR can be clinically significant since there is a very low probably of the disease progressing with ongoing therapy.
Part 4 – When to Switch to Second-Line Therapy
Dr. Moshe Talpaz. University of Michigan – Ann Arbor, discussed criteria for making a switch to a second line therapy. For patients that began treatment with Imatinib, switching to a second line therapy is considered when responses have been outside the parameters set in the European Leukemia Net (ELN) guidelines, or when adverse events/side effects cause extreme quality of life issues.
Dr. Talpaz also pointed out that when contemplating a switch, the patient’s past health history should be considered since second-line options carry potential side effects that might exacerbate additional adverse events. For example, one would not recommend Dasatinib to a patient that also had Cystic Fibrosis, due to the possibility of pleural effusion (PE), however remote PE might be. Nilotinib might not be recommended in patients that had heart conditions or disease due to the propensity for the drug to bring about Qt prolongation (a negative change in heart rhythm) in some patients.
The possibility of mutations should also be considered when contemplating which drug to use in the second-line setting. Each drug differs in its effectiveness among a variety of mutations, therefore screening should be done. Doing so will provide the patient with the best option for their unique case.
If a person’s general health is good (aside from their CML), other considerations might apply. For example, fasting schedules, and/or ease of taking therapy can greatly influence the outcome.
With the number of choices available today, patients are able to have access to the therapy that best suits their needs. Thus moving us closer to a personalized medicine approach.
Part 5 – T315I Mutations: Incidence, Implications, and Therapy
Neil Shah, M.D., from the University of California, SF shared the latest options for patients diagnosed with the T315I mutation. This mutation continues to be the bane of every researcher and specialist out there as it renders all current FDA approved therapies ineffective. Fortunately, there are drugs currently in trial that are showing efficacy in addressing this difficult mutation.
Dr. Shah began by discussing the details of why some patients lose their response to TKI (Tyrosine Kinase Inhibitor) therapy. Two clinical observations were considered, the first being drug resistance. Resistance can be attributed to a variety of things. Some patients experience drug resistance due to suboptimal dosing, either via attempts to lessen side effects, or in adequate serum levels of the drug in their blood. Others may have developed one or more of the over 100 BCR-ABL mutations. It should be noted that developing a mutation does not necessarily mean that TKI therapy is no longer effective. It simply means that it may be time to switch to another TKI or for dose escalation. Currently, only the dreaded T315I renders all TKIs ineffective.
Dr. Shah went on to discuss a variety of investigational options for patients with T315I. There is much optimism about the efficacy of these investigational drugs. All of which are also efficatious for patients that have experienced multiple TKI failures. Each of these drugs were discussed at length so that medical professionals could better understand the mechanism of action for each.
It was quite exciting to see the enthusiasm of the audience as each of these investigational drugs were discussed.
Part 6 – The Role and Timing of Allogeneic Stem Cell Transplantation in CML
The final presentation was brought by Dr John Goldman. Dr. Goldman is Emeritus Professor of Leukemia Biology at the Imperial College London, London England.
With the advent of TKI therapy, transplantation has been supplanted as an early, front-line option for those diagnosed with CML. There do remain to be cases for which stem cell transplant and Dr. Goldman outlined them for each phase of the disease. Generally, SCT is utilized when TKI failure has occurred, however, they failure needs to be defined. In advanced phase disease, SCT is an option for all eligible patients AFTER their disease has been restored to chronic phase. Although there is a return to CP, it is usually short-lived following the initial failure.
Dr. Goldman went on to say that the results of Allogeneic SCT have improved dramatically in recent years. He said that one must always remember that the decision to undertake a transplant depends on a variety of facts relevant to a particular transplant, such as patient age, the donor HLA match, and the patient’s agreement to proceed.
Prior to SCT, clinicians will recommend treating patients with any remaining TKIs, or secondary/cytotoxic drugs.
Dr. Goldman summarized his presentation with the following: Allogeneic SCT is no longer a routine, initial treatment for CML in chronic phases but has a definite role in treating those that have failed first and second-line TKIs. Additionally, it may be possible to predict if a patient is likely to fail a second-line TKI, at which time SCT should be the next recommended treatment. No standard protocol for chronic phase patients exists, and advanced phase patients should be offered SCT if at all possible.