http://www.ahdbonlin...se-finding-cure
Chronic Myeloid Leukemia: Are We Close to Finding a Cure?
The cure for chronic myeloid leukemia (CML) is a topic of intense debate among hematologists these days, not only the possibility of achieving it but what cure actually means.
"What do we mean by 'cure'?" asked Junia Melo, MD, PhD, Imperial College of Medicine, London, speaking at a CML education session at ASH 2011.
One position is that a cure is the eradication of every leukemic cell from the body; a second perspective holds that what is needed is an "operational cure," meaning the disappearance of all signs of the disease, so that there is no further impact on the patient's quality of life.
"The first concept is overly simplistic," said Dr Melo. "Not only is it difficult to achieve; it's impossible to prove." There is no assay that can ensure that every last leukemic cell present can be detected.
Dr Melo asked if a treatment-free cure is truly that important. "There are 3 things to look at: chronic toxicity with treatment and late-emerging toxicities; cost of continuing treatment; and the threat of lingering, although minimal, disease."
Toxicities and Cost of Continuing Treatment
One recent study has shown that many patients with CML are tired of receiving treatment. When asked to stratify their treatment's side effects, patients said they "minded very much" fatigue (29%), muscle cramps (30%), pain (30%), and edema (24%). "We need to consider this when we're keeping patients on treatment for years at a time," Dr Melo said.
The cost of years-long treatment is also no small matter. Dr Melo estimates that the cost to treat CML patients using tyrosine kinase inhibitors (TKIs) in the United Kingdom ranges from £18,000 to £32,000 ($27,000-$48,000) annually.
As for the lingering potential for relapse—should a few active leukemic cells survive treatment—what threshold of risk is acceptable? There is no way to say. "So, maybe an operational cure is only a partial success and we should aim higher."
Treating CML with an allogeneic transplant is defined as curative. However, as Dr Melo pointed out, although the relapse-free rate with transplant is as high as 70% at 10 years, only 25% of patients are able to find the necessary human leukocyte antigen-matched donor. Furthermore, those who receive a transplant risk developing chronic graft-versus-host disease, and, according to very sensitive testing methods, 30% of transplant patients still harbor aberrant BCR-ABL (potentially disease-causing) transcripts.
Can CML Actually Be Cured?
Accepting the premise that a cure cannot be proved, Dr Melo considered whether cures have been seen in practice. Two clinical trials involved patients who achieved a complete molecular response (CMR) and were allowed to stop treatment with TKIs—the CML8 trial and the STIM (Stop Imatinib) study. Both showed that approximately 40% of patients were able to discontinue treatment and maintain CMR for 5 years.
"This tells us that for some proportion of patients, the TKIs can be safely withdrawn," Dr Melo said, adding that stopping treatment in the STIM trial is estimated to have saved as much as €4 million ($5.2 million), "even in this short period of time."
In both trials, patients received imatinib. The potential for cure with second-generation TKIs may hold even greater promise (see below). In one study, 64% of patients in CMR who stopped treatment with dasatinib or nilotinib have maintained responses for 10 months of follow-up. "Although the numbers are very small [N = 33], it is still very encouraging," Dr Melo said.
Can Cures Be Predicted?
Evidence continues to accrue that some patients can be treatment-free and cured, but predicting who may be cured remains a challenge. A small subset of patients from the STIM trial who successfully stopped treatment (N = 66) displayed a few identifiable commonalities. Significant factors for treatment-free individuals with sustained CMR were lower Sokal prognostic scores, imatinib treatment >50 months, and (barely significant for reasons unknown) male sex.
The molecular mechanism of cure is also coming into focus. Citing a recent analysis of data from the IRIS (International Randomized IFN versus STI571) and TIDEL (Trial of Imatinib with Dose Escalation) trials (both with imatinib), Dr Melo favors the idea of a triphasic response to treatment that results in "stem-cell exhaustion," in which 3 distinct cancer-cell-killing time intervals have been observed. "In the first 3 to 4 months you kill all the mature cells, then after 3 to 4 years the progenitor cells die off, then finally you get to the (cancer-originating) stem cells."
"Can we consolidate CMR with more intense use of TKIs?" asked Dr Melo. Several approaches that are being considered include change of dose, schedule, and adding an immunotherapy. The answer may lie in new drugs that target the stem cells themselves.
"There are several new agents in development that target the oncogene BCR-ABL, stop the formation of stem cells, and induce apoptosis in quiescent cells," said Dr Melo. But if no method can ensure the detection of no residual, potentially life-threatening CML stem cells, then the reality of achieving a cure will remain a matter of faith and ongoing patient observation.
