Cure a Reality in Near Future?

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Nat Rev Clin Onc. 2011;8(3):1-2. © 2011 Nature Publishing Group

What are the practical implications for patients with CML in 2011? First and

foremost: caution. At this point the STIM data are preliminary and follow-up is

too short for changes in clinical practice. As with any experimental treatment,

patients who wish to stop imatinib should enroll in a controlled trial.

Can imatinib cure chronic myeloid leukemia (CML)? No other question in the field

of CML has been debated with the same fervor since it was recognized that some

patients with a complete molecular response (CMR, defined as consistently

negative tests for BCR-ABL transcripts in the blood), maintain this response

after discontinuation of therapy. As almost all of the patients in this original

report had previously been treated with interferon-a (IFN-a) it remained unclear

whether or not this response could be accomplished with imatinib alone.

Mahon and colleagues now report the first results of the Stop Imatinib (STIM)

trial, which enrolled 100 patients who discontinued imatinib after achieving and

maintaining CMR for 2 years or more, including 49 patients who had never

received IFN-a. Of the 69 patients with at least 12 months of follow-up (median

24 months), 42 (61%) experienced a re-emergence of BCR-ABL transcripts; the

remaining patients maintained their CMR. Factors independently associated with

recurrence were female sex, shorter duration of imatinib therapy and high Sokal

risk disease at diagnosis, whereas previous exposure to IFN-a was not relevant.

All but one of the recurrences occurred within 7 months of stopping imatinib,

and all patients with recurrent disease responded to imatinib rechallenge. This

finding suggests that stopping imatinib may be safe if done with close

monitoring, and that the term 'recurrence' should be used to distinguish this

situation from 'relapse', which implies progression despite continued therapy.

As it is possible to determine relatively early those patients whose disease is

destined to recur, one might be able to decrease the frequency of monitoring

once a patient has maintained CMR for a yet to be determined length of

follow-up.

Are patients with sustained CMR off imatinib truly cured of CML? At this point,

the answer is a qualified 'maybe'. First we have to be sure that what we are

seeing is indeed a genuine plateau and not a slow but inexorable attrition. A

study reported in 2010 using a patient-specific DNA-based assay found residual

leukemia in seven out of eight patients who maintained CMR after imatinib

discontinuation; it is quite possible that these seven patients will eventually

proceed to negativity but it is also possible that the apparent inability to

eradicate all residual BCR-ABL-positive cells is a sign that a patient's disease

will eventually recur. The second consideration is more conceptual: how do we

define 'cure'? A first thought would be to equate cure with the complete absence

of BCR-ABL. This definition is radical but impractical, as it cannot be tested

experimentally. Moreover, we know that highly sensitive assays can detect

BCR-ABL transcripts even in healthy volunteers. Thus, another concept of cure is

needed that takes account of the ability to safely discontinue treatment but not

the certainty of having annihilated all CML cells. In this frame of thinking,

cure would be defined as a likelihood of developing clinical CML that is no

different from the general population. The fact that occasional relapses have

occurred almost two decades after allogeneic stem-cell transplant suggests that

considerable observation time will be needed before making this call. the major

concern is that stopping imatinib in the absence of clonal extinction might lead

to renewed exposure of CML stem cells to BCR-ABL kinase activity, promoting

genomic instability and, ultimately, disease progression.

What tentative conclusions can we draw from this phenomenon about the disease

biology in the two groups? The behavior of the first cohort (those with early

recurrence) is consistent with the current concept of residual disease in

imatinib-treated CML. Leukemic progenitor cells, unlike stem cells, are

sensitive to imatinib suggesting that the reconstitution of leukemic

hematopoiesis at the expense of normal hematopoiesis may start immediately after

imatinib treatment is stopped.

What tentative conclusions can we draw from this phenomenon about the disease

biology in the two groups? The behavior of the first cohort (those with early

recurrence) is consistent with the current concept of residual disease in

imatinib-treated CML. Leukemic progenitor cells, unlike stem cells, are

sensitive to imatinib suggesting that the reconstitution of leukemic

hematopoiesis at the expense of normal hematopoiesis may start immediately after

imatinib treatment is stopped. More............

http://www.medscape.com/viewarticle/737431

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FYI,

Lottie Duthu