Chronic Myeloid Leukemia: Current Status and Controversies

In order to understand the controversies in chronic myeloid leukemia (CML), one must understand the current status of the disease. With the introduction of imatinib(Drug information on imatinib) mesylate (Gleevec), our knowledge of the biology of the disease, as well as treatment modalities, has changed. As Mughal and Goldman illustrate, we currently know extensive detail about the mechanisms involved in the development and progression of this disease. Short of developing a cure for CML, continuing investigation is un- covering important and useful information regarding the prognostic variables to be considered when making treatment decisions. Ironically, the old dilemma of who should receive a transplant and when is now more difficult. Managing a seemingly straightforward case is complex, and established clinical investigators have been humbled by their decisions. History
Twenty years ago, the natural course of CML, in the absence of effective treatment, was 3 to 5 years in chronic phase with the majority of patients progressing to accelerated and blast crisis phase and finally succumbing to their disease. Due to the grim outlook, investigators explored the role of stem cell transplant as a potential cure. Yet, even the seemingly optimal candidate had to face the real possibility of a toxic death. Those who were not candidates for transplant generally knew their eventual fate. Over the subsequent decade, the outlook became more hopeful. The use of interferon resulted in a few long-term remissions, and the toxicity of stem cell transplant improved, resulting in some cures. After another decade of advances, transplant modalities have expanded and outcomes have improved. But the major advance has been the introduction of imatinib. The aim of therapy is no longer to delay disease progression, but to eradicate it. Is that a legitimate goal? For most patients and investigators, any less is unacceptable. With higher standards come more difficult decisions. Therefore, it is imperative that physicians at least understand the data in order to make an informed decision. Imatinib
Imatinib has had a great impact on CML, at least in the short term, and the impressive response rates are summarized by Mughal and Goldman. The big question is: Will this translate into improved long-term survival rates despite the lack of molecular remissions? Many believe that imatinib does not induce a true cure, but as discussed in the article, a "functional cure" may be desirable if it results in good outcomes. Resistance to treatment is the overriding fear, and predicting who will become resistant may not always be possible; however, as more mechanisms are classified, strategies to overcome them will be developed. These mechanisms can be categorized in various ways. Some have used the terms upfront vs acquired. Because upfront resistance is extremely rare, investigation of the more common acquired resistance has been extensive. Mutations in either the adenosine(Drug information on adenosine) triphosphate binding pocket or regions of the tyrosine kinase domain, which weaken the imatinibtarget bond, represent the most common cause of resistance. Other mechanisms include overexpression or gene amplification of Bcr-Abl, as well as clonal evolution in both Philadelphia chromosome (Ph)- positive and Ph-negative clones. These processes underscore the importance of monitoring patient responses to imatinib by standard cytogenetics, fluorescence in situ hybridization, and polymerase chain reaction (PCR). Controversies arise from our attempts to overcome or prevent resistance. For example, investigators disagree about the starting dose of imatinib, ways to monitor response, and whether to combine imatinib with other agents. Recent results suggest that initial high doses of imatinib lead to more rapid, as well as more complete, cytogenetic and molecular responses, but we have yet to demonstrate that this strategy produces a longer survival.[1] The starting dose will remain controversial until a randomized trial is completed. Methods to monitor response have not yet been standardized. Many centers do not have the ability to perform quantitative PCR studies, nor are they consistently performed at centers that do. Therefore, many physicians rely on other clues when assessing individual responses. As mentioned, predictive factors for poor response may include the development of neutropenia during imatinib treatment[2] and the failure to achieve an early cytogenetic response. "Early," however, has not been defined, and investigators differ on that issue as well. Whether the upfront addition of other agents to imatinib therapy will improve overall survival remains to be determined. This may depend on which aberrant pathways predominate in individual patients. Expected response rates will vary, and large-scale improvements will be rare, particularly if these agents are used in subjects without the targeted defects. Transplant
What has remained constant for the last 20+ years is that stem cell transplant is the only established cure for CML. However, complications continue to represent a significant risk. Current efforts for improvement include decreasing transplant-related mortality and morbidity rates and the risk of relapse, and broadening the donor pool. The means to accomplish these goals involve achieving better control over graft-vs-host disease (GVHD) and potentially fatal infections, better defining the source of stem cells for specific situations, and improving results with matched unrelated donors as well as reduced-intensity conditioning regimens. Better supportive care has resulted in incremental improvements in early survival posttransplant. However, GVHD remains the biggest risk in transplant patients, not only as a significant cause of death, but as a persistent cause of serious morbidity. Unfortunately, GVHD is also the best clinical marker for the alloimmune reaction (graft-vs-leukemia) that has rendered this treatment effective in CML. For the last several years, a major goal of research has been to isolate GVHD from the graft-vs-leukemia effect, but this has proven to be very difficult. It has resulted in the development of reduced-intensity conditioning, a nonmyeloablative approach. As mentioned in the article, early data regarding reduced-intensity conditioning transplants are encouraging. In concert with this effort is that of providing more stem cell sources through unrelated donor searches. For patients in chronic phase, matched unrelated donor transplants are only slightly inferior to those from matched siblings.[3] Which stem cell source to utilize in patients-bone marrow or peripheral blood-is not clear. The advan- tages of each were discussed in the article and are currently being investigated in a randomized trial. Also controversial is how to utilize prior data regarding optimal transplant candidates, which, as mentioned, are outdated. Historically, we know that younger patients in early chronic phase fare best. With imatinib, will this trend change such that we can delay a transplant, or would we then lose our opportunity for cure? Most large centers have developed internal treatment algorithms, but definitive guidelines are not available. Both investigators and knowledgeable patients have personal biases that negate the opportunity for a randomized trial of frontline transplant vs imatinib therapy. Until the data mature regarding these options, decisions are difficult. At this time, this author's bias is to place the decision point box in Mughal and Goldman's Figure 4 after the initial imatinib therapy, so that the choice then becomes continued imatinib therapy or transplant. Conclusions
Ongoing investigation of the biology of CML will provide the means for making better decisions. Imatinib has enabled science to advance beyond the point of the Philadelphia chromosome. It has virtually removed the Bcr-Abl tyrosine kinase mechanism from the equation, unmasking (and/or perhaps creating) different aberrant pathways and fine-tuning our knowledge of CML biology. CML will continue to challenge us for many years to come. From past research, CML patients have gone from not having options to having multiple op- tions. Hopefully, the next era will represent a time when the proper curative option for each patient is obvious.